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Abstract:

Inhalation solutions for administration of beta 2-agonists or
combinations of muscarinic antagonists and beta 2-agonists for the
treatment of breathing disorders, such as COPD, are provided. The
inhalation solutions are administered by nebulization, particularly with
a high efficiency nebulizer.

Claims:

1. A method of treating a patient having chronic obstructive pulmonary
disease (COPD), comprising administering to the patient with a high
efficiency nebulizer a dose of formoterol, or a pharmaceutically
acceptable salt thereof, and a dose of glycopyrrolate, or a
pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the administration with the high
efficiency nebulizer produces an improved magnitude or duration of a
therapeutic effect in the patient compared to administration of
formoterol, or a pharmaceutically acceptable salt thereof, or
glycopyrrolate, or a pharmaceutically acceptable salt thereof, with a
conventional nebulizer, a metered dose inhaler, or a dry powder inhaler
as a monotherapy.

3. The method of claim 2, wherein the improved magnitude or duration of a
therapeutic effect comprises clinically meaningful bronchodilation for at
least 24 hours.

4. The method of claim 3, wherein the clinically meaningful
bronchodilation comprises an increase in trough FEV1 of at least 10%
or at least 100 mL above placebo.

5. The method of claim 1, wherein the administration with the high
efficiency nebulizer of formoterol, or a pharmaceutically acceptable salt
thereof, and glycopyrrolate, or a pharmaceutically acceptable salt
thereof, produces improved or reduced side effects in the patient
compared to administration of formoterol, or a pharmaceutically
acceptable salt thereof, or glycopyrrolate, or a pharmaceutically
acceptable salt thereof, with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler as a monotherapy.

6. The method of claim 1, wherein the dose of formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is less than half of an approved
therapeutic dose of formoterol, or a pharmaceutically acceptable salt
thereof, administered with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler.

7. The method of claim 1, wherein the dose of formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is about 0.5 μg to about 15 μg.

8. The method of claim 1, wherein the dose of formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is about 0.5 μg to about 2 μg.

9. The method of claim 1, wherein the dose of glycopyrrolate, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is less than half of an approved
therapeutic dose of glycopyrrolate, or a pharmaceutically acceptable salt
thereof, administered with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler.

10. The method of claim 1, wherein the dose of formoterol, or a
pharmaceutically acceptable salt thereof, and the dose of glycopyrrolate,
or a pharmaceutically acceptable salt thereof, is administered to the
patient twice daily.

11. A method of treating a patient having chronic obstructive pulmonary
disease (COPD), comprising administering to the patient with a high
efficiency nebulizer a dose of R,R-formoterol, or a pharmaceutically
acceptable salt thereof, and a dose of glycopyrrolate, or a
pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the administration with the high
efficiency nebulizer produces an improved magnitude or duration of a
therapeutic effect in the patient compared to administration of
R,R-formoterol, or a pharmaceutically acceptable salt thereof, or
glycopyrrolate, or a pharmaceutically acceptable salt thereof, with a
conventional nebulizer, a metered dose inhaler, or a dry powder inhaler
as a monotherapy.

13. The method of claim 12, wherein the improved magnitude or duration of
a therapeutic effect comprises clinically meaningful bronchodilation for
at least 24 hours.

14. The method of claim 13, wherein the clinically meaningful
bronchodilation comprises an increase in trough FEV1 of at least 10%
or at least 100 mL above placebo.

15. The method of claim 11, wherein the administration with the high
efficiency nebulizer of R,R-formoterol, or a pharmaceutically acceptable
salt thereof, and glycopyrrolate, or a pharmaceutically acceptable salt
thereof, produces improved or reduce d side effects in the patient
compared to administration of R,R-formoterol, or a pharmaceutically
acceptable salt thereof, or glycopyrrolate, or a pharmaceutically
acceptable salt thereof, with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler as a monotherapy.

16. The method of claim 11, wherein the dose of R,R-formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is less than half of an approved
therapeutic dose of R,R-formoterol, or a pharmaceutically acceptable salt
thereof, administered with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler.

17. The method of claim 11, wherein the dose of R,R-formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is about 0.5 μg to about 15 μg.

18. The method of claim 11, wherein the dose of R,R-formoterol, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is about 0.5 μg to about 2 μg.

19. The method of claim 11, wherein the dose of glycopyrrolate, or a
pharmaceutically acceptable salt thereof, administered to the patient
with the high efficiency nebulizer is less than half of an approved
therapeutic dose of glycopyrrolate, or a pharmaceutically acceptable salt
thereof, administered with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler.

20. The method of claim 11, wherein the dose of R,R-formoterol, or a
pharmaceutically acceptable salt thereof, and the dose of glycopyrrolate,
or a pharmaceutically acceptable salt thereof, is administered to the
patient twice daily.

Description:

[0001] This application is a continuation of U.S. patent application Ser.
No. 12/797,537, filed Jun. 9, 2010, which claims priority under 35 U.S.C.
§119(e) from U.S. Provisional Patent Application No. 61/185,524,
filed Jun. 9, 2009, and from U.S. Provisional Patent Application No.
61/185,528, filed Jun. 9, 2009, each of which is incorporated herein by
reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Chronic obstructive airway disease (COPD) is a pulmonary (lung)
disease characterized by chronic obstruction of the airways. COPD
encompasses emphysema and chronic bronchitis. Chronic bronchitis is
diagnosed where a patient suffers from chronic cough, mucus production,
or both, for at least three months in at least two successive years where
other causes of chronic cough have been excluded. In chronic bronchitis,
airway obstruction is caused by chronic and excessive secretion of
abnormal airway mucus, inflammation, and bronchospasm. Often chronic
bronchitis is exacerbated by frequent or chronic infection.

[0003] Emphysema involves the destruction of elastin in terminal
bronchioles, which leads to remodeling, destruction and ultimate collapse
of the airway walls. Patients with emphysema gradually lose the ability
to exhale, causing a rise in blood waste gasses (such as carbon dioxide),
a drop in blood oxygen, and a general degradation of patient stamina and
overall health. A characteristic of emphysema is permanent loss of
alveoli. Remodeling leads to permanent enlargement of the air spaces
distal to the terminal bronchioles, and destruction of terminal
bronchiole walls, though without fibrosis. Emphysema is progressive with
a poor prognosis. Since there is no known method for repairing elastin or
restoring the alveoli, therapy is generally palliative and persistent.

[0004] Most patients suffering from COPD have both emphysema and chronic
bronchitis. The standard of treatment for COPD includes maintenance
and/or rescue dosing of bronchodilator and/or anti-inflammatory aerosol
drugs. While most patients respond to treatment with metered dose
inhalers or dry powder inhalers, there is a subset of patients for whom
such options are not well-suited. Older and sicker COPD patients, for
example, often find it difficult to use, or do not experience therapeutic
benefit from the use of, metered dose inhalers or dry powder inhalers.

[0005] Dry powder inhalers are generally passive delivery devices, which
patients actuate by forceful, controlled inhalation through the mouth.
Metered dose inhalers, on the other hand, are in general active delivery
devices, which create an atomized mist by forcing a drug solution or
suspension through a nozzle under pressure. A patient activates the
metered dose inhaler by pressing an actuator and simultaneously breathing
in through the mouth in order to deposit the drug in the patient's lungs.
Patients whose motor skills are impaired or not fully developed will
often have trouble activating the device, coordinating their breathing,
and generally using metered dose inhalers. Patients who also have poor
inhalation capacity and control find dry powder inhalers to be difficult
to operate as well. Newer inhaler devices that are breath-actuated or
produce a soft mist are easier for patients to operate; but these newer
devices still require coordination and a breath-hold; and achievement of
sufficient lung deposition and distribution is reliant on only one or two
inhalations. For sicker and older COPD patients, nebulizer delivery of
their medicines is an important delivery option, since they can generally
receive a full dose regardless of disease state, because all that is
required is normal (tidal) breathing over multiple minutes.

[0006] There are two general categories of bronchodilators effective for
treating COPD--muscarinic antagonists and beta 2-agonists. Longer-acting
bronchodilators are preferred to shorter-acting bronchodilators due to
their superior efficacy and duration of effect, as well as favorable
impact on patient compliance.

[0007] Three FDA approved long-acting beta 2-agonists (so called LABAs)
that have been approved for use in COPD in the United States are
formoterol fumarate (Foradil®, Perforomist®), arformoterol
tartrate (Brovana®), and salmeterol xinafoate (Serevent®). Each
of these LABAs have only been approved for twice-daily dosing, having
demonstrated clinically meaningful bronchodilation with acceptable side
effects over only 12 hours. One LAB A, arformoterol tartrate,
demonstrated clinically meaningful bronchodilation over 24 hours in a
clinical trial, but with unacceptable side effects. R. Baumgartner, et
al., "Nebulized Arformoterol in Patients with COPD: A 12-Week,
Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo- and
Active-Controlled Trial," Clinical Therapeutics, Vol. 29, No. 2, 2007.

[0008] One long-acting muscarinic antagonist (so called LAMA) that has
been approved for use in COPD in the United States is tiotropium bromide
powder for inhalation (Spiriva®, NDA No. 021395, Boehringer
Ingelheim). Tiotropium bromide is available commercially only as a dry
powder, which is administered by a breath-activated inhaler. A similar
mode of administration is disclosed by Bannister et al. (U.S. Pat. No.
7,229,607) for administration of glycopyrronium bromide (glycopyrrolate)
as a dry powder. The '607 patent claims a method for achieving grater
than 20 hours of bronchodilation in a COPD patient by means of coated
particles in a dry powder formulation. The '607 patent distinguishes this
methodology from administration of a solution formulation of
glycopyrrolate, which is characterized as being unable to achieve
effective treatment of COPD for longer than 12 hours. For example,
Bannister et al. state: "Schroeckenstein et al., J. Allergy Clin.
Immunol, 1988; 82(1): 115-119, discloses the use of glycopyrrolate in an
aerosol formulation for treating asthma. A single administration of the
metered-dose glycopyrrolate aerosol achieved bronchodilation over a 12
hour period." Additionally, Bannister et al. admit: "Skorodin, Arch
Intern. Med, 1993; 153: 814 828, discloses the use of glycopyrrolate in
an aerosol formulation for the treatment of asthma and COPD. It is stated
that, in general, the quaternary ammonium anticholinergic compounds have
a duration of action of 4 to 12 hours. A dose of between 0.2 to 1.0 mg of
glycopyrrolate is recommended at 6 to 12 hour intervals." And the
inventors of the '607 patent also state: "Walker et al., Chest, 1987;
91(1): 49-51, also discloses the effect of inhaled glycopyrrolate as an
asthma treatment. Again, the duration of effective treatment is shown to
be up to 12 hours, although up to 8 hours appears to be maximal."

[0009] The combination of a LABA and a LAMA may offer synergistic
benefits. As of yet, no LABA/LAMA combinations have been approved by any
regulatory authority, although several are in development. There have
been numerous fixed combinations consisting of two active pharmaceutical
ingredients developed and approved for COPD (e.g. Advair®,
Combivent®, DuoNeb®), but in every case the dose, and the
frequency of dosing, approved was the same as that for the individual
active pharmaceutical ingredient monotherapies.

[0010] A sub-segment of the COPD population comprising the sickest and
oldest patients requires nebulizer delivery of their medicines because
they are unable to satisfactorily operate a metered dose or dry powder
inhaler, or because they experience superior therapeutic benefit from
nebulizer delivery of the medications. However, the treatment options for
these patients are limited. Two long-acting beta 2 agonist solution
formulations are approved for nebulizer delivery twice daily (B.I.D.),
and indicated for the maintenance treatment of COPD symptoms. However,
once-daily (Q.D.) dosing is preferable to B.I.D. There are no LAMAs
approved for nebulizer delivery. Ipratropium bromide is the only
muscarinic antagonist approved for nebulizer delivery in COPD
(monotherapy or in combination with albuterol), however ipratropium
+/-albuterol is indicated for administration four times per day (QID);
and QID dosing and long nebulization times of this short-acting agent is
inconvenient, leading to poor compliance and thus sub-optimal clinical
outcomes. Glycopyrrolate has been demonstrated to potentially be a safe
and effective bronchodilator that provides up to 12 hours of clinically
meaningful improvement in therapeutic bronchodilation in COPD patients
with acceptable side effects when delivered by a nebulizer. Longer acting
aerosol drugs have been demonstrated to generally be more efficacious and
result in better compliance compared to shorter acting drugs.
Furthermore, it has not been previously demonstrated that combining a
LABA, previously demonstrated to provide only 12 hours of clinically
meaningful duration of bronchodilation with acceptable side effects, with
a LAMA, that previously demonstrated only up to 12 hours of clinically
meaningful bronchodilation with acceptable side effects in a nebulizer,
can result in 24 hours of clinically meaningful bronchodilation with
acceptable side effects or a significantly improved therapeutic index.

[0011] There is thus a need for additional therapeutic options for the
treatment of COPD. There is a need for therapeutic options that offer
greater convenience, better efficacy, and/or better safety, especially
for the sub-population of COPD patients who require nebulizer delivery.
In particular there is a need for a nebulized beta 2-agonist that
provides more than 12 hours, and preferably at least 24 hours of
therapeutic benefit to COPD patients. There is also a need for a fixed
combination of a LABA/LAMA that provides 24 hours of therapeutic benefit
to COPD patients wherein the LABA and/or the LABA previously have been
demonstrated to provide only 12 hours of clinically meaningful
therapeutic benefit with acceptable side effects. And, there is a need
for a fixed combination of a LABA/LAMA wherein, although no improvement
in duration of therapeutic benefit may be seen compared to the individual
active monotherapies, a significant improvement is provided in the safety
profile. Heretofore, no methods, devices or systems have been suggested
that satisfies these needs.

[0012] There is a need for more effective approaches to treating COPD.

SUMMARY OF THE INVENTION

[0013] The invention provides methods of treating COPD and a device or
system adapted for such treatment. In particular, the invention provides
methods and systems for treating COPD by administering a long-acting beta
2-agonist (LABA) or a combination of a long-acting muscarinic antagonist
(LAMA) and a LABA to a patient in need of such treatment. Embodiments
described herein provide improved therapeutic efficacy (e.g. enhanced
duration and/or magnitude of therapeutic effect), improvements in the
side effects generally associated with LAMA and/or LABA therapy, and/or
improved patient compliance (e.g. due to improved convenience, reduced
side effects, improved overall feeling of wellness, etc.).

[0014] Provided herein is a method of treating a patient having chronic
obstructive pulmonary disease (COPD), comprising administering to the
patient, with a high efficiency nebulizer, a dose of a long-acting beta
2-agonist (LABA) that produces a significantly improved therapeutic
effect in the patient compared to administration of the same dose of the
LABA with a conventional nebulizer, metered dose inhaler or dry powder
inhaler. In some embodiments, administering the LABA with the high
efficiency nebulizer results in significantly improved magnitude or
duration of therapeutic effect, and/or significantly improved side
effects, compared to administering the LABA with a conventional
nebulizer, a metered dose inhaler, or a dry powder inhaler. In some
embodiments, the dose of the LABA is an amount of the LABA that produces
clinically meaningful bronchodilation for at least 24 hours when
administered with a high efficiency nebulizer, wherein the same LABA
produces significantly less than 24 hours clinically meaningful
bronchodilation when administered with a conventional nebulizer, a
metered dose inhaler or a dry powder inhaler. In some embodiments, the
clinically meaningful bronchodilation is an increase in trough FEV1
of at least 10% or at least 100 mL above placebo. In some embodiments,
the dose of the LABA is an amount of the LABA that produces clinically
meaningful bronchodilation for at least 24 hours, with acceptable side
effects, when administered with a high efficiency nebulizer, and wherein
a dose of the same LABA produces significantly less than 24 hours of
clinically meaningful bronchodilation, with acceptable side effects, when
administered to the lungs with a conventional nebulizer, a metered dose
inhaler or a dry powder inhaler. In some embodiments, the LABA that is
administered comprises formoterol, salmeterol, indacaterol, or a
pharmaceutically acceptable enantiomer and/or salt thereof.

[0015] Also provided herein is a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient a LABA, with a high efficiency nebulizer, wherein such
administration significantly improves the duration and/or magnitude of
therapeutic effect of the LABA, while retaining acceptable side effects,
compared to administering the same LABA administered with a conventional
nebulizer, metered dose inhaler or dry powder inhaler. In some
embodiments, administering the LABA with the high efficiency nebulizer
results in clinically meaningful bronchodilation for at least 24 hours,
with acceptable side effects, and wherein administering the same LABA
with a conventional nebulizer, metered dose inhaler or dry powder inhaler
results in significantly less than 24 hours of clinically meaningful
bronchodilation with acceptable side effects. In some embodiments, the
LABA is formoterol, salmeterol, or a pharmaceutically acceptable
enantiomer and/or salt thereof.

[0016] Also provided herein is a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient with a high efficiency nebulizer a reduced dose of a
long-acting beta 2-agonist (LABA), wherein said reduced dose of LABA is
less than half of an approved therapeutic dose of LABA administered with
a conventional nebulizer, a metered dose inhaler, or a dry powder inhaler
and wherein the reduced dose of LABA provides (a) similar magnitude of
therapeutic effect; (b) similar duration of therapeutic effect; or both
(a) and (b), compared with administration of the approved therapeutic
dose of LABA with a conventional nebulizer, a metered dose inhaler, or a
dry powder inhaler. In some embodiments, the LABA is formoterol,
salmeterol, indacaterol, or a pharmaceutically acceptable enantiomer
and/or salt thereof. In some embodiments, administration of the LABA with
the high efficiency nebulizer results in reduced side effects compared to
the approved therapeutic dose of the LABA administered with a
conventional nebulizer, a metered dose inhaler, or a dry powder inhaler.
In some embodiments, the LABA is formoterol, or a pharmaceutically
acceptable salt thereof, and is administered at a dose of less than about
10 μg. In some embodiments, the LABA is R,R-formoterol, or a
pharmaceutically acceptable salt thereof, and is administered at a dose
of less than about 7.5 μg of enantiomerically pure R,R-formoterol. In
some embodiments, the LABA is salmeterol, or a pharmaceutically
acceptable salt thereof, and is administered at a dose of less than about
25 μg.

[0017] Also provided is a method of treating a patient having chronic
obstructive pulmonary disease (COPD), comprising administering to the
patient with a high efficiency nebulizer a dose of a long-acting beta
2-agonist (LABA), wherein said administration provides: (i) an increased
magnitude of therapeutic effect; (ii) an increased duration of
therapeutic effect; and/or (iii) reduced side effects, as compared to
administration of a dose of the LABA, with a conventional nebulizer,
sufficient to achieve the same respirable or deposited dose as is
achieved with the high efficiency nebulizer. In some embodiments, the
LABA is formoterol, salmeterol, indacaterol, or a pharmaceutically
acceptable enantiomer and/or salt thereof.

[0018] Also described herein is a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient with a high efficiency nebulizer a dose of long-acting beta
2-agonist (LABA), wherein said administration provides substantially the
same magnitude and duration of therapeutic effect, and reduced side
effects, as compared to administration of a dose of the LABA, with a
conventional nebulizer, metered dose inhaler or dry powder inhaler that
is necessary to achieve the same respirable or deposited dose as is
achieved with the high efficiency nebulizer. In some embodiments, the
LABA is formoterol, salmeterol, indacaterol, or a pharmaceutically
acceptable enantiomer and/or salt thereof.

[0019] Also provided herein is a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient, with a high efficiency nebulizer, a dose of a combination of
an amount of a long-acting beta 2-agonist (LABA) and an amount of a
long-acting muscarinic antagonist (LAMA), wherein administering the dose
of the combination with the high efficiency nebulizer is effective to
produce a significantly improved therapeutic effect in the patient
compared to administration of the LABA with a nebulizer as a monotherapy,
and/or compared to administration of the LAMA with a nebulizer as a
monotherapy. In some embodiments, administering the dose of the
combination with the high efficiency nebulizer results in significantly
improved magnitude or duration of therapeutic effect, and/or
significantly improved side effects, compared to administering the LABA
with a nebulizer as a monotherapy and/or compared to administering the
LAMA with a nebulizer as a monotherapy. In some embodiments, the dose of
the combination refers to the nominal, respirable or deposited dose of
the combination. In some embodiments, the dose of the combination is an
amount of the LABA that produces clinically meaningful bronchodilation
for significantly less than 24 hours, with acceptable side effects, when
administered with a nebulizer and/or an amount of the LAMA that produces
clinically meaningful bronchodilation for significantly less than 24
hours, with acceptable side effects, when administered with a nebulizer,
wherein the dose of the combination produces clinically meaningful
bronchodilation for at least 24 hours, with acceptable side effects, of
when administered with a high efficiency nebulizer. In some embodiments,
administering the dose of the combination with the high efficiency
nebulizer is effective to produce a significantly improved therapeutic
effect in the patient compared to administering the LABA with a
conventional nebulizer as a monotherapy, and/or compared to administering
the LAMA with a conventional nebulizer as a monotherapy. In some
embodiments, the clinically meaningful bronchodilation is an increase in
trough FEV1 of at least 10% or 100 mL above placebo. In some
embodiments, the LABA is formoterol, salmeterol, indacaterol, or a
pharmaceutically acceptable enantiomer and/or salt thereof. In some
embodiments, the LAMA is glycopyrrolate or a pharmaceutically acceptable
enantiomer and/or salt thereof. In some embodiments, the LABA is
formoterol or a pharmaceutically acceptable enantiomer and/or salt
thereof and the LAMA is glycopyrrolate or a pharmaceutically acceptable
enantiomer and/or salt thereof.

[0020] Also provided is a method of treating a patient having chronic
obstructive pulmonary disease (COPD), comprising administering to the
patient, with a high efficiency nebulizer, a dose of a combination of an
amount of a long-acting beta 2-agonist (LABA) and an amount of a
long-acting muscarinic antagonist (LAMA), wherein administering the dose
of the combination with the high efficiency nebulizer is effective to
produce a significantly improved therapeutic effect in the patient
compared to administration of the LABA with a nebulizer, metered dose
inhaler, or dry powder inhaler as a monotherapy, and/or compared to
administration of the LAMA with a nebulizer, soft mist inhaler, metered
dose inhaler, or dry powder inhaler as a monotherapy. In some
embodiments, administering the dose of the combination with the high
efficiency nebulizer results in significantly improved magnitude or
duration of therapeutic effect, and/or significantly improved side
effects, compared to administering the LABA with a nebulizer, metered
dose inhaler, or dry powder inhaler as a monotherapy and compared to
administering the LAMA with a nebulizer as a monotherapy. In some
embodiments, the dose of the combination refers to the nominal,
respirable or deposited dose of the combination. In some embodiments, the
dose of the combination is an amount of the LABA that produces clinically
meaningful bronchodilation with acceptable side effects for significantly
less than 24 hours when administered with a nebulizer, metered dose
inhaler, or dry powder inhaler and/or an amount of the LAMA that produces
clinically meaningful bronchodilation with acceptable side effects for
significantly less than 24 hours when administered with a nebulizer, soft
mist inhaler, metered dose inhaler, or dry powder inhaler, wherein the
dose of the combination produces clinically meaningful bronchodilation
with acceptable side effects for at least 24 hours when administered with
a high efficiency nebulizer. In some embodiments, administering the dose
of the combination with the high efficiency nebulizer is effective to
produce a significantly improved therapeutic effect in the patient
compared to administration of the LABA with a conventional nebulizer as a
monotherapy, and/or compared to administration of the LAMA with a
conventional nebulizer as a monotherapy. In some embodiments, the
clinically meaningful bronchodilation is an increase in trough FEV1
of at least 10% or 100 mL above placebo. In some embodiments, the LABA is
formoterol, salmeterol, indacaterol, or a pharmaceutically acceptable
enantiomer and/or salt thereof. In some embodiments, the LAMA is
glycopyrrolate or a pharmaceutically acceptable enantiomer and/or salt
thereof. In some embodiments, the LABA is formoterol, salmeterol,
indacaterol, or a pharmaceutically acceptable enantiomer and/or salt
thereof and the LAMA is glycopyrrolate or a pharmaceutically acceptable
enantiomer and/or salt thereof.

[0021] Also provided herein is a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising twice per day
administering to the patient, with a high efficiency nebulizer, a dose of
a combination of an amount of a long-acting beta 2-agonist (LABA) and an
amount of a long-acting muscarinic antagonist (LAMA), wherein
administering the dose of the combination twice per day with the high
efficiency nebulizer is effective to elicit significantly reduced side
effects in the patient compared to twice per day administration of the
LABA with a nebulizer as a monotherapy, and/or compared to twice per day
administration of the LAMA with a nebulizer as a monotherapy. In some
embodiments, the amount of the LABA in the combination dose is
significantly reduced compared to a twice per day dose of the LABA as a
monotherapy. In some embodiments, the amount of the LAMA in the
combination dose is significantly reduced compared to a twice per day
dose of the LAMA as monotherapy.

[0022] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient an amount of formoterol or a combination of
glycopyrrolate and formoterol sufficient to produce a therapeutic effect
for at least 24 hours with acceptable side effects.

[0023] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer a nominal,
respirable, or deposited dose of formoterol, wherein said administration
provides: (i) an increased magnitude of therapeutic effect; (ii) an
increased duration of therapeutic effect; and/or (iii) reduced side
effects, as compared to administration of the same nominal, respirable,
or deposited dose of formoterol with a conventional nebulizer. Some
embodiments described herein provide a method of treating a patient
having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer a nominal
dose of formoterol, wherein said administration provides: an increased
magnitude and/or duration of therapeutic effect and therapeutically
acceptable side effects, as compared to administration of the same
nominal dose of formoterol with a conventional nebulizer. Some
embodiments described herein provide a method of treating a patient
having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer a
respirable or deposited dose of formoterol, wherein said administration
provides: (i) a similar magnitude and/or duration of therapeutic effect;
and reduced side effects, as compared to administration of the same
respirable or deposited dose of formoterol with a conventional nebulizer.

[0024] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer an amount
of a LABA, e.g. formoterol, effective to provide a therapeutic effect,
with acceptable side effects, for at least 24 hours.

[0025] Some embodiments described herein provide a method of treating a
patient having a respiratory condition, comprising administering to the
patient with a high efficiency nebulizer a nominal, respirable, or
deposited dose of a LABA, wherein said administration provides: (i) an
increased magnitude of therapeutic effect; (ii) an increased duration of
therapeutic effect; and/or (iii) reduced side effects, as compared to
administration of the same nominal, respirable, or deposited dose of said
LABA with a conventional nebulizer.

INCORPORATION BY REFERENCE

[0026] Any and all references cited herein are incorporated herein by
reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

[0027] Unless defined otherwise, all technical and scientific terms used
herein have the same meanings as are commonly understood by one of skill
in the art to which the inventions described herein belong. All
publications, patents, and patent applications mentioned in this
specification are herein incorporated by reference to the same extent as
if each individual publication, patent, or patent application was
specifically and individually indicated to be incorporated by reference.

DEFINITION OF TERMS

[0028] As used herein, the term "about" is used synonymously with the term
"approximately." Illustratively, the use of the term "about" with regard
to a certain therapeutically effective pharmaceutical dose indicates that
values slightly outside the cited values, e.g., plus or minus 0.1% to
10%, which are also effective and safe.

[0029] As used herein, the terms "comprising", "including", "such as", and
"for example" (or "e.g.") are used in their open, non-limiting sense.

[0030] As used herein "meg" means micrograms, and is synonymous with
"μg" or "ug". One microgram (mcg) is 0.001 mg, or 0.000001 g.

[0031] As used herein, the phrase "consisting essentially of" is a
transitional phrase used in a claim to indicate that the following list
of ingredients, parts or process steps must be present in the claimed
composition, machine or process, but that the claim is open to unlisted
ingredients, parts or process steps that do not materially affect the
basic and novel properties of the invention.

[0032] "Nominal dose", as used herein, refers to the loaded dose, which is
the amount of active pharmaceutical ingredient ("API") in an inhalation
device prior to administration to the patient. The volume of solution
containing the nominal dose is referred to as the "fill volume".

[0033] "AUC.sub.(0-t)HEN" as used herein, refers to the area under a
blood plasma concentration curve up to the last time point for the
nominal dose of active pharmaceutical ingredient (API) administered with
a high efficiency nebulizer.

[0034] "AUC.sub.(0-t).sup.Conv" as used herein, refers to the area under a
blood plasma concentration curve up to the last time point for a nominal
dose of active pharmaceutical ingredient (API) administered with a
conventional nebulizer.

[0035] "AUC.sub.(0-∞)HEN" as used herein, refers to the area
under a blood plasma concentration curve for a nominal dose of active
pharmaceutical ingredient (API) administered with a high efficiency
nebulizer.

[0036] "AUC.sub.(0-∞).sup.Conv" as used herein, refers to the area
under a blood plasma concentration curve for a nominal dose of active
pharmaceutical ingredient (API) administered with a conventional
nebulizer [AUC.sub.(0-∞).sup.Conv].

[0037] "Substantially the same nominal dose" as used herein, means that a
first nominal dose of an active pharmaceutical ingredient (API) contains
approximately the same number of millimoles of the muscarinic antagonist
as a second nominal dose of the muscarinic antagonist.

[0038] "Substantially the same nominal dose" as used herein, means that a
first nominal dose of an active pharmaceutical ingredient (API) contains
approximately the same number of millimoles of the muscarinic antagonist
as a second nominal dose of the muscarinic antagonist.

[0039] "Bioavailability" as used herein, refers to the amount of unchanged
drug that reaches the systemic circulation. By definition, the
bioavailability of an intravenous solution containing the active
pharmaceutical ingredient (API) is 100%.

[0040] "Enhanced lung deposition," as used herein, refers to an increase
in drug deposition (deposited lung dose) arising out of, for example, the
improved efficiency of drug delivery with a high efficiency nebulizer. In
general, a high efficiency nebulizer will produce a drug cloud having a
greater respirable fraction than a conventional nebulizer. While not
wishing to be bound by theory, it is considered that a greater respirable
fraction will permit greater lung deposition and concomitantly lower
oropharyngeal deposition of the drug. In some embodiments, it is
considered that reduced oropharyngeal deposition of drug will reduce
local side effects, for example dry mouth.

[0041] "Deposited dose" or "deposited lung dose" is the amount of
muscarinic antagonist deposited in the lung. The deposited dose or
deposited lung dose may be expressed in absolute terms, for example the
number of μg of API deposited in the lungs. The deposited lung dose
may be expressed as a percentage of the nominal dose deposited in the
lungs. The deposited lung dose may also be expressed in relative terms,
for example comparing the mass of API deposited in the lungs with a high
efficiency nebulizer to the mass of API deposited in the lungs with a
conventional nebulizer.

[0042] "CmaxHEN" as used herein, refers to the maximum blood
plasma concentration for a nominal dose of the active pharmaceutical
ingredient (API) administered with a high efficiency nebulizer.

[0043] "Cmax.sup.Conv" as used herein, refers to the maximum blood
plasma concentration for a nominal dose of the active pharmaceutical
ingredient (API) administered with a conventional nebulizer.

[0044] "Enhanced pharmacokinetic profile" means an improvement in some
pharmacokinetic parameter. Pharmacokinetic parameters that may be
improved include, AUClast, AUC.sub.(0-∞)Tmax, and
optionally a Cmax. In some embodiments, the enhanced pharmacokinetic
profile may be measured quantitatively by comparing a pharmacokinetic
parameter obtained for a nominal dose of an active pharmaceutical
ingredient (API) administered with one type of inhalation device (e.g. a
high efficiency nebulizer) with the same pharmacokinetic parameter
obtained with the same nominal dose of active pharmaceutical ingredient
(API) administered with a different type of inhalation device.

[0045] "Blood plasma concentration" refers to the concentration of an
active pharmaceutical ingredient (API) in the plasma component of blood
of a subject or patient population.

[0046] "Respiratory condition," as used herein, refers to a disease or
condition that is physically manifested in the respiratory tract,
including, but not limited to, chronic obstructive pulmonary disease
(COPD), bronchitis, chronic bronchitis, emphysema, asthma, or reactive
airway disorder (RAD).

[0047] "Patient" refers to the animal (especially mammal) or human being
treated.

[0048] "Muscarinic antagonist" refers to antimuscarinic agents, which are
compounds that have the ability to inhibit the action of the
neurotransmitter acetylcholine by blocking its binding to muscarinic
cholinergic receptors. These agents can be long-acting or short-acting.
Long-acting muscarinic antagonists have a therapeutic effect lasting
greater than about 6 hours. Some long-acting muscarinic antagonists
include, but are not limited to, glycopyrrolate, tiotropium, aclidinium,
trospium, darotropium, QAT 370, GSK 233705, GSK 573719, GSK 656398,
TD4208, BEA 218 or a pharmaceutical acceptable derivative, salt,
enantiomer, diastereomer, or racemic mixture thereof. Short-acting
muscarinic antagonists have a therapeutic effect for less than about 6
hours. Some short-acting muscarinic antagonists include, but are not
limited to, ipratropium, oxitropium, or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or racemic mixture thereof.
In some embodiments, the "muscarinic antagonist" is glycopyrrolate,
tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK 656398, BEA2180,
ipratropium, oxitropium, oxybutynin or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or a pharmaceutical
acceptable derivative, salt, enantiomer, diastereomer, or racemic mixture
thereof.

[0049] "Nebulizer," as used herein, refers to a device that turns
medications, compositions, formulations, suspensions, and mixtures, etc.
into a fine mist for delivery to the lungs. Nebulizers may also be
referred to as atomizers.

[0050] "Drug absorption" or simply "absorption" typically refers to the
process of movement of drug from site of delivery of a drug across a
barrier into a blood vessel or the site of action, e.g., a drug being
absorbed in the pulmonary capillary beds of the alveoli.

[0051] [TmaxHEN] as used herein, refers to the amount of time
necessary for a nominal dose of an active pharmaceutical ingredient (API)
to attain maximum blood plasma concentration after administration with a
high efficiency nebulizer.

[0052] [T1/2] Half-life: T1/2 in reference to the elimination rate of a
drug, such as a muscarinic antagonist (e.g. glycopyrrolate) is the amount
of time necessary for the drug's plasma concentration to drop to one-half
of its initial plasma concentration.

[0053] [Tmax.sup.Conv] as used herein, refers to the amount of time
necessary for a nominal dose of an active pharmaceutical ingredient (API)
to attain maximum blood plasma concentration after administration with a
conventional nebulizer.

[0054] The term "treat" and its grammatical variants (e.g. "to treat,"
"treating," and "treatment") refer to administration of an active
pharmaceutical ingredient to a patient with the purpose of ameliorating
or reducing the incidence of one or more symptoms of a condition or
disease state in the patient. Such symptoms may be chronic or acute; and
such amelioration may be partial or complete. In the present context,
treatment entails administering a muscarinic antagonist (optionally in
combination with a beta 2-agonist) to a patient via a pulmonary
inhalation route.

[0055] The term "prophylaxis" refers to administration of an active
pharmaceutical ingredient to a patient with the purpose of reducing the
occurrence or recurrence of one or more acute symptoms associated with a
disease state in the patient. In the present context, prophylaxis entails
administering a muscarinic antagonist (optionally in combination with a
beta 2-agonist) to a patient via a pulmonary inhalation route. Thus,
prophylaxis includes reduction in the occurrence or recurrence rate of
acute exacerbations in chronic obstructive pulmonary disease (COPD).
However, prophylaxis is not intended to include complete prevention of
onset of a disease state in a patient who has not previously been
identified as suffering from a pulmonary condition or disease; nor does
prophylaxis include prevention of pulmonary cancer.

[0056] As used herein, a difference is "significant" if a person skilled
in the art would recognize that the difference is probably real. In some
embodiments, significance may be determined statistically--in which case
two measured parameters may be referred to as statistically significant.
In some embodiments, statistical significance may be quantified in terms
of a stated confidence interval (CI), e.g. greater than 90%, greater than
95%, greater than 98%, etc. In some embodiments, statistical significance
may be quantified in terms of a p value, e.g. less than 0.5, less than
0.1, less than 0.05, etc. The person skilled in the art will recognize
these expressions of significance and will know how to apply them
appropriately to the specific parameters that are being compared.

[0057] In some embodiments described herein an active pharmaceutical
ingredient (API) is a muscarinic antagonist. In some embodiments, the API
is substantially free of other bronchodilating agents, such as beta
2-agonists, like formoterol, salmeterol and salbutamol (albuterol). In
this context, "substantially free of other bronchodilating agents"
indicates that the solution contains no other bronchodilating agent or
contains less than a quantity of another bronchodilating agent that would
be sufficient to materially affect the properties of the muscarinic
antagonist solution. In some embodiments, the API is a muscarinic
antagonist (optionally in combination with a beta 2-agonist and/or in
combination with an anti-inflammatory agent which could include a
corticosteroid or a non-steroidal anti-inflammatory drug (NSAID)). In
some embodiments, the API is free of other bronchodilating agents, such
as beta 2-agonists, like formoterol, salmeterol and salbutamol
(albuterol). In this context, "free of other bronchodilating agents"
means that the solution contains no other bronchodilating agent than the
recited muscarinic antagonist, or contains less than a detectable amount
of the other bronchodilating agents.

[0058] Beta-2 adrenergic agonists are agents that mimic epinephrine in
their interaction with β2-adrenergic receptors. Thus, beta-2
adrenergic agonists are also referred to in the literature as
beta-mimetics. A long-acting β2 adrenergic agonist (LABA) is an
active agent that has an effect similar to that of adrenaline, but with
longer lasting effect (e.g. at least about 12 hr.) In the lung, LABAs
stimulate adenlyate cyclase activity, closing calcium channels, and
relaxing smooth muscle, thereby relieving bronchospasm. The following are
generally classified as LABAs in the lung: bambuterol; bitolterol;
carbuterol; clenbuterol; fenoterol; formoterol; hexoprenaline; ibuterol;
indacaterol, pirbuterol; procaterol; reproterol; salmeterol; sulfonterol;
tolubuterol;
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]-amino}ethyl-
]-2(3H-benzothiazolone;
1-(2-fluoro4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino-
]ethanol; 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidaz-
olyl)-2-methyl-2-butylamino]ethanol;
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol;
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-propylamino]ethanol;
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol;
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
, 2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol;
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e; 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,
or 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)et-
hanol; or the racemates, enantiomers, diastereomers, or mixtures thereof,
optionally in the form of their pharmacologically-compatible acid
addition salts. In particular, formoterol may be present as the
enantiomerically pure (at least about 90%) R,R-formoterol (or a suitable
salt thereof), which is also referred to herein as arformoterol. As used
herein "racemic formoterol" refers to the approximately 50:50 mixture of
R,R-formoterol and its enantiomer S,S-formoterol. Salmeterol may be
present as the enantiomerically pure (at least about 90%) R-salmeterol or
as "racemic salmeterol," which is an approximately 50:50 mixture of
R-salmeterol and S-salmeterol or a suitable salt thereof.

[0059] Muscarinic Antagonists are agents that have the ability to inhibit
the action of the neurotransmitter acetylcholine by blocking its binding
to muscarinic cholinergic receptors. These agents can be long-acting or
short-acting. Long-acting muscarinic antagonists (LAMAs) have a
therapeutic effect lasting greater than about 6 hours. Some long-acting
muscarinic antagonists include, but are not limited to, glycopyrrolate,
R,R-glycopyrrolate, tiotropium, aclidinium, trospium, QAT 370, GSK,
233705, GSK 656398, BEA 218 or a pharmaceutical acceptable derivative,
salt, enantiomer, diastereomer, or racemic mixture thereof. Short-acting
muscarinic antagonists have a therapeutic effect for less than about 6
hours. Some short-acting muscarinic antagonists include, but are not
limited to, ipratropium, oxitropium, or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or racemic mixture thereof.
In some embodiments, the "muscarinic antagonist" is glycopyrrolate,
tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK 656398, BEA2180,
ipratropium, oxitropium, oxybutynin or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or a pharmaceutical
acceptable derivative, salt, enantiomer, diastereomer, or racemic mixture
thereof. In some embodiments, the muscarinic antagonist is
glycopyrrolate. In some embodiments, the muscarinic antagonist is racemic
glycopyrrolate; in other embodiments the muscarinic antagonist is
enriched in either the S,S- or R,R-enantiomer of glycopyrrolate. In some
embodiments, the muscarinic antagonist is at least 55%, at least 60%, at
least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at
least 99% or at least 99.5% enantiomerically pure R,R-glycopyrrolate.

[0060] Where a compound is mentioned herein without qualification of its
physical form (e.g. enantiomer, salt and/or polymorphic form), the
intended meaning is the compound in any of its known, possible forms.

[0061] "Monotherapy" refers to administration of an active pharmaceutical
agent, e.g. a muscarinic antagonist as the sole active ingredient. This
distinguishes monotherapy from combination therapy, in which two active
pharmaceutical agents, e.g. a muscarinic antagonist and a LABA, are
combined in a single therapeutic regime, e.g. by co-administration in a
single dosage form, or by serial administration.

[0062] As used herein "combination" refers to a mixture or serially
administered compositions. A mixture may be formed as a unit dose during
the manufacturing process; a mixture may also be formed by combination of
two separate unit doses prior to administration of the mixture to a
patient. A combination may also refer to separate unit doses administered
serially in a time frame that may be considered a single dosing
event--e.g. less than about 30 minutes, less than about 20 minutes, or
less than about 10 minutes.

[0063] A "standard dose" of a drug is either: (a) if the drug has been
approved by a governmental body (such as the United States Food and Drug
Administration), a government approved dose of the drug; or (b) if the
drug has not been approved, a minimum therapeutically effective dose of
the drug. A "minimum therapeutically effective dose" is the lowest dose
administered with a conventional nebulizer that provides a therapeutic
effect for a period of at least 12 hours, with acceptable side effects,
in a patient population. For formoterol, the standard dose is 20 μg of
formoterol administered as the fumarate salt by nebulization with a
conventional nebulizer twice per day (B.I.D.) For arformoterol
(R,R-formoterol), the standard dose is 15 μg of arformoterol
administered as the tartrate salt with a conventional nebulizer twice per
day (B.I.D.).

[0064] In some embodiments described herein an active pharmaceutical
ingredient (API) is a LABA or a muscarinic antagonist in combination with
a LABA, such as formoterol (racemate), arformoterol, salmeterol,
clenbuterol, etc.

[0065] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient, with a high efficiency nebulizer, a dose of
a long-acting beta 2-agonist (LABA) that produces a significantly
improved therapeutic effect in the patient compared to administration of
the same dose of the LABA with a conventional nebulizer. In some
embodiments, administering the LABA with the high efficiency nebulizer
results in significantly improved magnitude or duration of therapeutic
effect, and/or significantly improved side effects, compared to
administering the LABA with a conventional nebulizer, a metered dose
inhaler, or a dry powder inhaler. In some embodiments, the dose of the
LABA is an amount of the LABA that produces clinically meaningful
bronchodilation for at least 24 hours when administered with a high
efficiency nebulizer, wherein the same LABA produces significantly less
than 24 hours (e.g. less than 20 hours, less than 18 hours, less than 16
hours or 12 hours or less) clinically meaningful bronchodilation when
administered with a conventional nebulizer, a metered dose inhaler or a
dry powder inhaler. In some embodiments, the clinically meaningful
bronchodilation is an increase in trough FEV1 of at least 10% or at
least 100 mL above placebo. In some embodiments, the dose of the LABA is
an amount of the LABA that produces clinically meaningful
bronchodilation, with acceptable side effects, for at least 24 hours when
administered with a high efficiency nebulizer, and wherein the same LABA
produces significantly less than 24 hours (e.g. less than about 20 hours,
less than about 18 hours, less than about 16 hours, or 12 hours or less)
clinically meaningful bronchodilation, with acceptable side effects, when
administered to the lungs with a conventional nebulizer, a metered dose
inhaler or a dry powder inhaler. In some embodiments, wherein the LABA
that is administered comprises formoterol, salmeterol, or a
pharmaceutically acceptable enantiomer and/or salt thereof.

[0066] Some embodiments provide a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient a LABA with a high efficiency nebulizer that significantly
improves the duration and/or magnitude of therapeutic effect of the LABA,
while retaining acceptable side effects, compared to the same LABA
administered with a conventional nebulizer, metered dose inhaler or dry
powder inhaler. In some embodiments, the LABA administered with the high
efficiency nebulizer results in clinically meaningful bronchodilation for
at least 24 hours with acceptable side effects, and wherein the same LABA
administered by a conventional nebulizer, metered dose inhaler or dry
powder inhaler results in significantly less than 24 hours (e.g. less
than about 20 hours, less than about 18 hours, less than about 16 hours,
or 12 hours or less) of clinically meaningful bronchodilation with
acceptable side effects. In some embodiments, the LABA is formoterol,
salmeterol, or a pharmaceutically acceptable enantiomer and/or salt
thereof.

[0067] In some embodiments, the formoterol dose is delivered in a fill
volume of about 0.5 mL or less. In some embodiments, the formoterol dose
is delivered in about 3 min. or less. In some embodiments, the formoterol
is a 50:50 mixture of R,R-formoterol and S,S-formoterol. In some
embodiments, the formoterol dose is less than about 10 μg.

[0068] In some embodiments, the formoterol dose is about 0.5 μg to
about 8 μg, about 1 μg to about 8 μg, about 2 μg to about 8
μg, about 3 μg to about 8 μg, about 4 μg to about 8 μg,
about 5 μg to about 8 μg, about 6 μg to about 8 μg, about 0.5
μg to about 6 μg, about 1 μg to about 6 μg, about 2 μg to
about 6 μg, about 4 μg to about 6 μg, about 0.5 μg to about 5
μg, about 1 μg to about 5 μg, about 2 μg to about 5 μg,
about 3 μg to about 5 μg, about 4 μg to about 5 μg, about 0.5
μg to about 4 μg, about 1 μg to about 4 μg, about 2 μg to
about 4 μg, about 0.5 μg, about 1 μg, about 2 μg, about 3
μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about
8 μg or about 9 μg.

[0069] In some embodiments, the formoterol is an enantiomerically enriched
formoterol, which is greater than 90% enantiomerically pure
R,R-formoterol. In some embodiments, the enantiomerically enriched
formoterol is greater than 92%, greater than 93%, greater than 94%,
greater than 95%, greater than 96%, greater than 97%, greater than 98%,
about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about
99.6%, about 99.7%, about 99.8% or about 99.9% of R,R-formoterol.

[0070] In some embodiments, the formoterol dose is less than about 7.5
μg of enantiomerically pure R,R-formoterol. In some embodiments, the
formoterol dose is about 0.25 μg to about 7 μg, about 0.5 μg to
about 7 μg, about 1 μg to about 7 μg, about 2 μg to about 7
μg, about 3 μg to about 7 μg, about 4 μg to about 7 μg,
0.25 μg to about 6 μg, about 0.5 μg to about 6 μg, about 1
μg to about 6 μg, about 2 μg to about 6 μg, about 3 μg to
about 6 μg, about 4 μg to about 6 μg, about 0.25 μg to about
5 μg, about 0.5 μg to about 5 μg, about 1 μg to about 5
μg, about 2 μg to about 5 μg, about 3 μg to about 5 μg,
about 4 μg to about 5 μg, about 0.25 μg to about 4 μg, about
0.5 μg to about 4 μg, about 1 μg to about 4 μg, about 2 μg
to about 4 μg, about 0.25 μg to about 2 μg, about 0.5 μg to
about 2 μg, about 1 μg to about 2 μg, about 0.25 μg to about
1 μg, about 0.25 μg, about 0.5 μg, about 1 μg, about 2 μg,
about 3 μg, about 4 μg, about 5 μg or about 6 μg of
R,R-formoterol.

[0071] Some embodiments provide a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient with a high efficiency nebulizer an amount of formoterol
sufficient to produce a therapeutic effect with acceptable side effects
for at least 24 hours.

[0072] Some embodiments provide a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising administering to
the patient with a high efficiency nebulizer an amount of formoterol or a
combination of glycopyrrolate and formoterol sufficient to produce a
therapeutic effect with acceptable side effects for at least 24 hours. In
some embodiments the duration of therapeutic effect is at least 28 hours,
at least 30 hours, at least 32 hours or at least 36 hours. In some
embodiments, the side effects are reduced compared to: (a) an approved
dose of formoterol; (b) a minimally effective dose of glycopyrrolate; or
(c) both (a) and (b). In some embodiments, the reduced side effects
include one or more of the following: (a) side effects associated with
formoterol; (b) side effects associated with glycopyrrolate. In some
embodiments, the reduced side effects include at least one of the
following: airway hyperreactivity (hypersensitivity), angina, anorexia,
anxiety, backaches, blurred vision, bradycardia, central stimulation,
chest discomfort (e.g. chest pain), coughing, diarrhea, dizziness,
drowsiness, drying or irritation of the oropharynx (such as dry mouth
(xerostomia)), dyspnea, excitement, fatigue, flushing, hand tremors,
headache, hoarseness, hypotension and palpitations, impotence, increased
heart rate, insomnia, mental confusion, muscle cramps, muscle tremors,
nausea, nervousness, palpitations, sweating, tachycardia, unusual taste,
urinary hesitancy and retention, vertigo, vomiting, weakness, and
wheezing. In some embodiments, the nominal dose of glycopyrrolate is less
than about 100 μg to about 1600 μg, e.g. about 25 μg to about
500 μg or about 50 μg to about 300 μg. In some embodiments, the
nominal dose. In some embodiments, the nominal dose of formoterol is
about 1 to about 20 μg. In some embodiments, the formoterol is a 50:50
mixture of R,R- and S,S-formoterol or at least 90% enantiomerically pure
R,R-formoterol. In some embodiments, the formoterol is some mixture of
R,R- and S,S-formoterol of a ratio between 100:0 and 0:100. In some
embodiments, the mixture is at least about 60%, at least about 70%, at
least about 80%, at least about 90%, at least about 95%, at least about
98%, at least about 99% or at least about 99.5% enantiomerically pure
R,R-formoterol. In some embodiments, the combination is delivered with a
high efficiency nebulizer. In some embodiments, the combination has a
fill volume of ˜0.5 mL or less. In some embodiments, the
combination is delivered in about 3 minutes or less. In some embodiments,
the combination is delivered with a conventional nebulizer. Some
embodiments provide a system or device adapted or adaptable to carry out
the method of treatment. Some embodiments provide a unit dose, which may
be used in one of the foregoing methods, comprising an effective amount
of a muscarinic antagonist and a LABA in a pharmaceutically acceptable
diluent. In some embodiments such unit dose may be contained in a kit
comprising at least one additional dose.

[0073] Some embodiments provide a method of treating a patient having a
respiratory condition, comprising administering to the patient with a
high efficiency nebulizer a reduced dose of a long acting beta agonist
(LABA), wherein said reduced dose of LABA is less than half of a minimum
effective therapeutic dose of said LABA administered with a conventional
nebulizer, and which provides (a) similar magnitude of therapeutic
effect; (b) similar duration of therapeutic effect; or both (a) and (b),
compared with administration of the minimum effective therapeutic dose of
said LABA with a conventional nebulizer.

[0074] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a nebulizer a combination of a nominal
dose of glycopyrrolate and a nominal dose of formoterol, wherein said
administration produces: (a) an increased magnitude of therapeutic
effect; and (b) reduced side effects, as compared to administration, with
the same nebulizer, of: (1) said nominal dose of glycopyrrolate alone; or
(2) said nominal dose of formoterol alone.

[0075] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer a reduced
dose of a long-acting beta 2-agonist (LABA), wherein said reduced dose of
LABA is less than half of an approved therapeutic dose of LABA
administered with a conventional nebulizer, a metered dose inhaler, or a
dry powder inhaler and wherein the reduced dose of LABA provides (a)
similar magnitude of therapeutic effect; (b) similar duration of
therapeutic effect; or both (a) and (b), compared with administration of
the approved therapeutic dose of LABA with a conventional nebulizer, a
metered dose inhaler, or a dry powder inhaler. In some embodiments, the
LABA is formoterol, salmeterol, or a pharmaceutically acceptable
enantiomer and/or salt thereof. In some embodiments, administration of
the LABA with the high efficiency nebulizer results in reduced side
effects compared to the approved therapeutic dose of the LABA
administered with a conventional nebulizer, a metered dose inhaler, or a
dry powder inhaler. In some embodiments, the LABA is formoterol, or a
pharmaceutically acceptable salt thereof, and is administered at a dose
of less than about 10 μg. In some embodiments, the LABA is
R,R-formoterol, or a pharmaceutically acceptable salt thereof, and is
administered at a dose of less than about 7.5 μg of enantiomerically
pure R,R-formoterol. In some embodiments, the LABA is salmeterol, or a
pharmaceutically acceptable salt thereof, and is administered at a dose
of less than about 25 μg.

[0076] Some embodiments described herein provide a method of treating a
patient having a respiratory condition, comprising administering to the
patient with a high efficiency nebulizer a nominal, respirable, or
deposited dose of LABA, wherein said administration provides: (i) an
increased magnitude of therapeutic effect; (ii) an increased duration of
therapeutic effect; and/or (iii) reduced side effects, as compared to
administration of the same nominal, respirable, or deposited dose of LABA
with a conventional nebulizer. In some embodiments, the LABA dose is
delivered in a fill volume of about 0.5 mL or less. In some embodiments,
the LABA dose is delivered in about 3 min. or less. In some embodiments,
the LABA is a 50:50 mixture of R,R-formoterol and S,S-formoterol. In some
embodiments, the formoterol is an enantiomerically enriched formoterol,
which is greater than 90% enantiomerically pure R,R-formoterol
(arformoterol). In some embodiments, the LABA is selected from the group
consisting of formoterol (50:50 mixture of R,R- and S,S-formoterol),
salmeterol (50:50 mixture of R- and S-salmeterol), R-salmeterol,
R,R-formoterol, bambuterol, clenbuterol or indacaterol, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
respiratory condition.

[0077] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a high efficiency nebulizer a dose of a
long-acting beta 2-agonist (LABA), wherein said administration provides:
(i) an increased magnitude of therapeutic effect; (ii) an increased
duration of therapeutic effect; and/or (iii) reduced side effects, as
compared to administration of a dose of the LABA, with a conventional
nebulizer, that achieves the same respirable or deposited dose as is
achieved with the high efficiency nebulizer. In some embodiments, the
LABA is formoterol, salmeterol, or a pharmaceutically acceptable
enantiomer and/or salt thereof. In some embodiments, there is provided a
method of treating a patient having chronic obstructive pulmonary disease
(COPD), comprising administering to the patient with a high efficiency
nebulizer a dose of long-acting beta 2-agonist (LABA), wherein said
administration provides substantially the same magnitude and duration of
therapeutic effect, and reduced side effects, as compared to
administration of a dose of the LABA, with a conventional nebulizer,
metered dose inhaler or dry powder inhaler that is necessary to achieve
the same respirable or deposited dose as is achieved with the high
efficiency nebulizer. In some embodiments, the LABA is formoterol,
salmeterol, indacaterol, or a pharmaceutically acceptable enantiomer
and/or salt thereof.

[0078] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient, with a high efficiency nebulizer, a dose of
a combination of an amount of a long-acting beta 2-agonist (LABA) and an
amount of a long-acting muscarinic antagonist (LAMA), wherein the dose of
the combination is effective to produce a significantly improved
therapeutic effect in the patient compared to administration of the LABA
with a nebulizer as a monotherapy, and compared to administration of the
LAMA with a nebulizer as a monotherapy. In some embodiments, the method
comprises administering the dose of the combination with the high
efficiency nebulizer results in significantly improved magnitude or
duration of therapeutic effect, and/or significantly improved side
effects, compared to administering the LABA with a nebulizer as a
monotherapy and compared to administering the LAMA with a nebulizer as a
monotherapy. In some embodiments, the dose of the combination refers to
the nominal, respirable or deposited dose of the combination. In some
embodiments, the dose of the combination is an amount of the LABA that
produces clinically meaningful bronchodilation with acceptable side
effects for significantly less than 24 hours when administered with a
nebulizer and/or an amount of the LAMA that produces clinically
meaningful bronchodilation with acceptable side effects for significantly
less than 24 hours when administered with a nebulizer, wherein the dose
of the combination produces clinically meaningful bronchodilation with
acceptable side effects of 24 hours or more when administered with a high
efficiency nebulizer. In some embodiments, the clinically meaningful
bronchodilation is an increase in trough FEV1 of at least 10% or 100
mL above placebo. In some embodiments, the LABA is formoterol,
salmeterol, indacaterol, or a pharmaceutically acceptable enantiomer
and/or salt thereof. In some embodiments, the LAMA is glycopyrrolate or a
pharmaceutically acceptable enantiomer and/or salt thereof. In some
embodiments, the LABA is formoterol or a pharmaceutically acceptable
enantiomer and/or salt thereof and the LAMA is glycopyrrolate or a
pharmaceutically acceptable enantiomer and/or salt thereof. In some
embodiments, said administration produces: (a) an increased duration of
therapeutic effect; and (b) reduced, similar or acceptable side effects,
as compared to administration, with the same nebulizer, of: (1) said
nominal dose of glycopyrrolate alone; and (2) said nominal dose of
formoterol alone. In some embodiments, said administration results in a
duration of therapeutic effect greater than about 20 hr, greater than
about 22 hr or at least about 24 hr. In some embodiments the duration of
therapeutic effect is at least 12, 18, 20, 24, 28, 30, 32 or 36 hr. In
some embodiments, the increased magnitude of effect is greater than 5%
higher than provided by: (1) said nominal dose of glycopyrrolate alone;
and (2) said nominal dose of formoterol alone. In some embodiments, the
combination is administered with a high efficiency nebulizer. In some
embodiments, the combination is administered in a fill volume of about
0.5 mL or less. In some embodiments, the combination is administered in
about 3 minutes or less. In some embodiments, the combination is
administered with a conventional nebulizer. Some embodiments provide a
system or device adapted or adaptable to carry out the method of
treatment. Some embodiments provide a unit dose, which may be used in one
of the foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0079] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient, with a high efficiency nebulizer, a dose of
a combination of an amount of a long-acting beta 2-agonist (LABA) and an
amount of a long-acting muscarinic antagonist (LAMA), wherein the dose of
the combination is effective to produce a significantly improved
therapeutic effect in the patient compared to administration of the LABA
with a nebulizer, metered dose inhaler, or dry powder inhaler as a
monotherapy, and compared to administration of the LAMA with a nebulizer,
metered dose inhaler, or dry powder inhaler as a monotherapy. In some
embodiments, the method comprises administering the dose of the
combination with the high efficiency nebulizer results in significantly
improved magnitude or duration of therapeutic effect, and/or
significantly improved side effects, compared to administering the LABA
with a nebulizer, metered dose inhaler, or dry powder inhaler as a
monotherapy and compared to administering the LAMA with a nebulizer as a
monotherapy. In some embodiments, the dose of the combination refers to
the nominal, respirable or deposited dose of the combination. In some
embodiments, the dose of the combination is an amount of the LABA that
produces clinically meaningful bronchodilation with acceptable side
effects for significantly less than 24 hours when administered with a
nebulizer metered dose inhaler, or dry powder inhaler and/or an amount of
the LAMA that produces clinically meaningful bronchodilation with
acceptable side effects for significantly less than 24 hours when
administered with a nebulizer, wherein the dose of the combination
produces clinically meaningful bronchodilation with acceptable side
effects of 24 hours or more when administered with a high efficiency
nebulizer. In some embodiments, the clinically meaningful bronchodilation
is an increase in trough FEV1 of at least 10% or 100 mL above
placebo. In some embodiments, the LABA is formoterol, salmeterol,
indacaterol, or a pharmaceutically acceptable enantiomer and/or salt
thereof. In some embodiments, the LAMA is glycopyrrolate or a
pharmaceutically acceptable enantiomer and/or salt thereof. In some
embodiments, the LABA is salmeterol, indacaterol, or a pharmaceutically
acceptable enantiomer and/or salt thereof and the LAMA is glycopyrrolate
or a pharmaceutically acceptable enantiomer and/or salt thereof.

[0080] In some embodiments, said administration produces: (a) similar or
increased magnitude and/or duration of therapeutic effect; and (b)
reduced side effects, compared to administration, with the same
nebulizer, of: (1) said standard dose of glycopyrrolate alone; and (2)
said standard dose of formoterol alone. In some embodiments, said
administration produces: (a) similar or increased magnitude and/or
duration of therapeutic effect; and (b) reduced side effects, compared to
administration, with the same nebulizer, of: (1) said standard dose of
glycopyrrolate alone; and (3) a combination of said standard dose of
glycopyrrolate and said standard dose of formoterol. In some embodiments,
said administration produces: (a) similar or increased magnitude and/or
duration of therapeutic effect; and (b) reduced side effects, compared to
administration, with the same nebulizer, of: (1) said standard dose of
glycopyrrolate alone; and (2) said standard dose of formoterol alone; and
(3) a combination of said standard dose of glycopyrrolate and said
standard dose of formoterol.

[0081] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of (A) a reduced dose of
glycopyrrolate; and/or (B) a reduced dose of formoterol, wherein (I) said
reduced dose of glycopyrrolate is significantly less than a standard dose
of glycopyrrolate; and (II) said reduced dose of formoterol is
significantly less than a standard dose of formoterol, and wherein said
administration produces: (a) increased magnitude and/or duration of
therapeutic effect; and (b) reduced side effects, compared to
administration, with a conventional nebulizer, of: (1) said standard dose
of glycopyrrolate alone; or (2) said standard dose of formoterol alone.

[0082] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of a dose of glycopyrrolate and a dose
of formoterol, wherein said administration produces: (a) similar or
increased magnitude and/or duration of therapeutic effect; and (b)
reduced side effects, compared to administration, in a conventional
nebulizer, of: (1) the equivalent respirable dose of glycopyrrolate; 2)
the equivalent respirable dose of formoterol; or 3) the combination of
the equivalent respirable doses of glycopyrrolate and formoterol. In some
embodiments, said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of glycopyrrolate alone; and (2) said standard dose of
formoterol alone.

[0083] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient an amount of a combination of a LAMA and a
LABA sufficient to produce a therapeutic effect with acceptable side
effects for at least 24 hours. In some embodiments, the side effects are
reduced compared to: (a) a minimum therapeutically effective dose of said
LABA; (b) a minimum therapeutically effective dose of said LAMA; or (c)
both (a) and (b). In some embodiments, the reduced side effects include
one or more of the following: (a) side effects associated with a LABA;
(b) side effects associated with a LAMA; or (c) both (a) and (b). In some
embodiments, the reduced side effects include at least one or more of the
following: airway hyperreactivity (hypersensitivity), angina, anorexia,
anxiety, backaches, blurred vision, bradycardia, central stimulation,
chest discomfort (e.g. chest pain), coughing, diarrhea, dizziness,
drowsiness, drying or irritation of the oropharynx (such as dry mouth
(xerostomia)), dyspnea, excitement, fatigue, flushing, hand tremors,
headache, hoarseness, hypotension and palpitations, impotence, increased
heart rate, insomnia, mental confusion, muscle cramps, muscle tremors,
nausea, nervousness, palpitations, sweating, tachycardia, unusual taste,
urinary hesitancy and retention, vertigo, vomiting, weakness, and
wheezing. In some embodiments, the combination is delivered with a high
efficiency nebulizer. In some embodiments, the combination has a fill
volume of ˜0.5 mL or less. In some embodiments, the combination is
delivered in about 3 minutes or less. In some embodiments, the
combination is delivered with a conventional nebulizer. In some
embodiments, (a) said LAMA is glycopyrrolate, tiotropium, aclidinium,
trospium, QAT370, GSK233705, GSK 656398, or BEA2180, or a
pharmaceutically acceptable derivative, salt, enantiomer, diastereomer,
or racemic mixture thereof; and (b) said LABA is formoterol (such as
racemic formoterol, i.e. a 50:50 mixture of R,R- and S,S-formoterol),
salmeterol (50:50 mixture of R- and S-salmeterol), R-salmeterol,
R,R-formoterol, bambuterol, clenbuterol or indacaterol, or a
pharmaceutically acceptable derivative, salt, enantiomer, diastereomer,
or racemic mixture thereof. Some embodiments provide a system or device
adapted or adaptable to carry out the method of treatment. Some
embodiments provide a unit dose, which may be used in one of the
foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0084] Some embodiments provided herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a nebulizer a combination of a nominal
dose of a LAMA and a nominal dose of a LABA, wherein said administration
produces: (a) an increased magnitude of therapeutic effect; and (b)
reduced side effects, as compared to administration, with the same
nebulizer, of: (1) said nominal dose of said LAMA alone; or (2) said
nominal dose of said LABA alone. In some embodiments, said administration
produces: (a) an increased magnitude of therapeutic effect; and (b)
reduced side effects, as compared to administration, with the same
nebulizer, of: (1) said nominal dose of said LAMA alone; and (2) said
nominal dose of said LABA alone. In some embodiments, the magnitude of
therapeutic effect is compared at about 12 hr post delivery. In some
embodiments, the duration of therapeutic effect is at least about 12 hr.
In some embodiments, the increased magnitude of effect is greater than 5%
higher than provided by: (1) said nominal dose of said LAMA alone; and
(2) said nominal dose of said LABA alone. In some embodiments, the
combination is administered with a high efficiency nebulizer. In some
embodiments, the combination is administered in a fill volume of about
0.5 mL or less. In some embodiments, the combination is administered in
about 3 minutes or less. In some embodiments, the combination is
administered with a conventional nebulizer. In some embodiments, (a) said
LAMA is glycopyrrolate, tiotropium, aclidinium, trospium, QAT370,
GSK233705, GSK 656398, or BEA2180, or a pharmaceutically acceptable
derivative, salt, enantiomer, diastereomer, or racemic mixture thereof;
and (b) said LABA is formoterol (such as racemic formoterol, i.e. a 50:50
mixture of R,R- and S,S-formoterol), salmeterol (50:50 mixture of R- and
S-salmeterol), R-salmeterol, R,R-formoterol, bambuterol, clenbuterol or
indacaterol, or a pharmaceutically acceptable derivative, salt,
enantiomer, diastereomer, or racemic mixture thereof. Some embodiments
provide a system or device adapted or adaptable to carry out the method
of treatment. Some embodiments provide a unit dose, which may be used in
one of the foregoing methods, comprising an effective amount of a
muscarinic antagonist and a LABA in a pharmaceutically acceptable
diluent. In some embodiments such unit dose may be contained in a kit
comprising at least one additional dose.

[0085] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a
nebulizer a combination of a nominal dose of a LAMA and a nominal dose of
a LABA, wherein said administration produces: (a) an increased duration
of therapeutic effect; and (b) reduced, similar or acceptable side
effects, as compared to administration, with the same nebulizer, of: (1)
said nominal dose of said LAMA alone; or (2) said nominal dose of said
LABA alone. In some embodiments, said administration produces: (a) an
increased duration of therapeutic effect; and (b) reduced, similar or
acceptable side effects, as compared to administration, with the same
nebulizer, of: (1) said nominal dose of said LAMA alone; and (2) said
nominal dose of said LABA alone. In some embodiments, said administration
results in a duration of therapeutic effect greater than about 20 hr,
greater than about 22 hr or at least about 24 hr. In some embodiments,
the increased magnitude of effect is greater than 5% higher than provided
by: (1) said nominal dose of said LAMA alone; and (2) said nominal dose
of said LABA alone. In some embodiments, the combination is administered
with a high efficiency nebulizer. In some embodiments, the combination is
administered in a fill volume of about 0.5 mL or less. In some
embodiments, the combination is administered in about 3 minutes or less.
In some embodiments, the combination is administered with a conventional
nebulizer. In some embodiments, (a) said LAMA is glycopyrrolate,
tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK 656398, or
BEA2180, or a pharmaceutically acceptable derivative, salt, enantiomer,
diastereomer, or racemic mixture thereof; and (b) said LABA is formoterol
(such as racemic formoterol, i.e. a 50:50 mixture of R,R- and
S,S-formoterol), salmeterol (50:50 mixture of R- and S-salmeterol),
R-salmeterol, R,R-formoterol, bambuterol, clenbuterol or indacaterol, or
a pharmaceutically acceptable derivative, salt, enantiomer, diastereomer,
or racemic mixture thereof. Some embodiments provide a system or device
adapted or adaptable to carry out the method of treatment. Some
embodiments provide a unit dose, which may be used in one of the
foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0086] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a
nebulizer a combination of (A) a nominal dose of a LAMA and (B) a nominal
dose of a LABA, wherein at least one of the nominal doses of said LAMA or
said LABA is significantly less than a standard dose; and wherein said
administration produces: (a) similar or increased magnitude and/or
duration of therapeutic effect; and (b) reduced side effects, compared to
administration, with the same nebulizer, of: (1) said standard dose of
said LAMA alone; or (2) said standard dose of said LABA alone; or (3) a
combination of said standard dose of said LAMA and said standard dose of
said LABA.

[0087] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of: (A) a reduced dose of said LAMA;
and/or (B) a reduced dose of said LABA, wherein (I) said reduced dose of
said LAMA is significantly less than a standard dose of said LAMA; and
(II) said reduced dose of said LABA is significantly less than a standard
dose of said LABA, and wherein said administration produces: (a)
increased magnitude and/or duration of therapeutic effect; and (b)
reduced side effects, compared to administration, with a conventional
nebulizer, of: (1) said standard dose of said LAMA alone; or (2) said
standard dose of said LABA alone. In some embodiments, said
administration produces: (a) similar or increased magnitude and/or
duration of therapeutic effect; and (b) reduced side effects, compared to
administration, with the same nebulizer, of: (1) said standard dose of
said LAMA alone; and (2) said standard dose of said LABA alone. In some
embodiments, said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of said LAMA alone; and (3) a combination of said
standard dose of said LAMA and said standard dose of said LABA. In some
embodiments, said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of said LAMA alone; and (2) said standard dose of said
LABA alone; and (3) a combination of said standard dose of said LAMA and
said standard dose of said LABA.

[0088] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of a dose of said LAMA and a dose of
said LABA, wherein said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, in a conventional nebulizer, of: (1)
the equivalent respirable dose of said LAMA; 2) the equivalent respirable
dose of said LABA; or 3) the combination of the equivalent respirable
doses of said LAMA and LABA. In some embodiments, said administration
produces: (a) similar or increased magnitude and/or duration of
therapeutic effect; and (b) reduced side effects, compared to
administration, with the same nebulizer, of: (1) said standard dose of
said LAMA alone; and (2) said standard dose of said LABA alone. In some
embodiments, said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of said LAMA alone; and (3) a combination of said
standard dose of said LAMA and said standard dose of said LABA. In some
embodiments, said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of said LAMA alone; and (2) said standard dose of said
LABA alone; and (3) a combination of said standard dose of said LAMA and
said standard dose of said LABA. In some embodiments, the nominal dose of
said LABA is significantly less than a standard dose of said LABA and the
standard dose of said LABA is a government approved dose of said LABA
administered with the same nebulizer. In some embodiments, the nominal
dose of said LAMA is significantly less than a standard dose of said LAMA
and the standard dose of said LAMA is a minimum effective therapeutic
dose of said LAMA administered with the same nebulizer. In some
embodiments, the nominal dose of said LABA is significantly less than a
standard dose of said LABA and the standard dose of said LABA is a
government approved dose of said LABA administered with the same
nebulizer; and wherein the nominal dose of said LAMA is significantly
less than a standard dose of said LAMA and the standard dose of said LAMA
is a minimum effective therapeutic dose of said LAMA administered with
the same nebulizer. In some embodiments, the duration of therapeutic
effect is at least about 20 hr, at least about 22 hr or at least about 24
hr.

[0089] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient an amount of a combination of glycopyrrolate
and formoterol sufficient to produce a therapeutic effect with reduced
side effects for at least 24 hours, wherein the side effects are reduced
compared to: (a) an approved dose of formoterol; (b) a minimally
effective dose of glycopyrrolate; or (c) both (a) and (b). In some
embodiments, the reduced side effects include one or more of the
following: (a) side effects associated with formoterol; (b) side effects
associated with glycopyrrolate. In some embodiments, the reduced side
effects include at least one or more of the following: airway
hyperreactivity (hypersensitivity), angina, anorexia, anxiety, backaches,
blurred vision, bradycardia, central stimulation, chest discomfort (e.g.
chest pain), coughing, diarrhea, dizziness, drowsiness, drying or
irritation of the oropharynx (such as dry mouth (xerostomia)), dyspnea,
excitement, fatigue, flushing, hand tremors, headache, hoarseness,
hypotension and palpitations, impotence, increased heart rate, insomnia,
mental confusion, muscle cramps, muscle tremors, nausea, nervousness,
palpitations, sweating, tachycardia, unusual taste, urinary hesitancy and
retention, vertigo, vomiting, weakness, and wheezing. In some
embodiments, the nominal dose of glycopyrrolate is less than about 100
μg to about 1600 μg. In some embodiments, the nominal dose of
formoterol is about 1 to about 20 μg.

[0090] In some embodiments, the formoterol dose is less than about 7.5
μg of enantiomerically pure R,R-formoterol. In some embodiments, the
formoterol dose is about 0.25 μg to about 7 μg, about 0.5 μg to
about 7 μg, about 1 μg to about 7 μg, about 2 μg to about 7
μg, about 3 μg to about 7 μg, about 4 μg to about 7 μg,
0.25 μg to about 6 μg, about 0.5 μg to about 6 μg, about 1
μg to about 6 μg, about 2 μg to about 6 μg, about 3 μg to
about 6 μg, about 4 μg to about 6 μg, about 0.25 μg to about
5 μg, about 0.5 μg to about 5 μg, about 1 μg to about 5
μg, about 2 μg to about 5 μg, about 3 μg to about 5 μg,
about 4 μg to about 5 μg, about 0.25 μg to about 4 μg, about
0.5 μg to about 4 μg, about 1 μg to about 4 μg, about 2 μg
to about 4 μg, about 0.25 μg to about 2 μg, about 0.5 μg to
about 2 μg, about 1 μg to about 2 μg, about 0.25 μg to about
1 μg, about 0.25 μg, about 0.5 μg, about 1 μg, about 2 μg,
about 3 μg, about 4 μg, about 5 μg or about 6 μg of
R,R-formoterol.

[0091] In some embodiments, the formoterol is a 50:50 mixture of R,R- and
S,S-formoterol or at least 90% enantiomerically pure R,R-formoterol. In
some embodiments, the combination is delivered with a high efficiency
nebulizer. In some embodiments, the combination has a fill volume of
˜0.5 mL or less. In some embodiments, the combination is delivered
in about 3 minutes or less. In some embodiments, the combination is
delivered with a conventional nebulizer. Some embodiments provide a
system or device adapted or adaptable to carry out the method of
treatment. Some embodiments provide a unit dose, which may be used in one
of the foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0092] Some embodiments described herein provide a method of treating a
patient having chronic obstructive pulmonary disease (COPD), comprising
administering to the patient with a nebulizer a combination of a nominal
dose of glycopyrrolate and a nominal dose of formoterol, wherein said
administration produces: (a) an increased magnitude of therapeutic
effect; and (b) reduced side effects, as compared to administration, with
the same nebulizer, of: (1) said nominal dose of glycopyrrolate alone; or
(2) said nominal dose of formoterol alone, and wherein said
administration produces. In some embodiments, the magnitude of
therapeutic effect is compared at about 12 hr post delivery. In some
embodiments, the duration of therapeutic effect is at least about 12 hr,
at least about 18 hr, at least about 20 hr or at least about 24 hr. In
some embodiments, the increased magnitude of effect is greater than 5%
higher than provided by: (1) said nominal dose of glycopyrrolate alone;
and (2) said nominal dose of formoterol alone. In some embodiments, the
combination is administered with a high efficiency nebulizer. In some
embodiments, the combination has a fill volume of about 0.5 mL or less.
In some embodiments, the combination is administered in about 3 minutes
or less. In some embodiments, the combination is administered with a
conventional nebulizer. Some embodiments provide a system or device
adapted or adaptable to carry out the method of treatment. Some
embodiments provide a unit dose, which may be used in one of the
foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0093] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a
nebulizer a combination of a nominal dose of glycopyrrolate and a nominal
dose of formoterol, wherein said administration produces: (a) an
increased duration of therapeutic effect; and (b) reduced, similar or
acceptable side effects, as compared to administration, with the same
nebulizer, of: (1) said nominal dose of glycopyrrolate alone; or (2) said
nominal dose of formoterol alone. In some embodiments, said
administration produces a duration of therapeutic effect greater than
about 20 hr, greater than about 22 hr or at least about 24 hr. In some
embodiments, the increased magnitude of effect is greater than 5% higher
than provided by: (1) said nominal dose of glycopyrrolate alone; and (2)
said nominal dose of formoterol alone. In some embodiments, the
combination is administered with a high efficiency nebulizer. In some
embodiments, the combination has a fill volume of about 0.5 mL or less.
In some embodiments, the combination is administered in about 3 minutes
or less. In some embodiments, the combination is administered with a
conventional nebulizer. Some embodiments provide a system or device
adapted or adaptable to carry out the method of treatment. Some
embodiments provide a unit dose, which may be used in one of the
foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0094] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a
nebulizer a combination of (A) a nominal dose of glycopyrrolate and (B) a
nominal dose of formoterol, wherein at least one of the nominal doses of
glycopyrrolate or formoterol is significantly less than a standard dose;
and wherein said administration produces: (a) similar or increased
magnitude and/or duration of therapeutic effect; and (b) reduced side
effects, compared to administration, with the same nebulizer, of: (1)
said standard dose of glycopyrrolate alone; (2) said standard dose of
formoterol alone; and (3) a combination of said standard dose of
glycopyrrolate and said standard dose of formoterol. In some embodiments,
the reduced side effects include at least one or more of the following:
airway hyperreactivity (hypersensitivity), angina, anorexia, anxiety,
backaches, blurred vision, bradycardia, central stimulation, chest
discomfort (e.g. chest pain), coughing, diarrhea, dizziness, drowsiness,
drying or irritation of the oropharynx (such as dry mouth (xerostomia)),
dyspnea, excitement, fatigue, flushing, hand tremors, headache,
hoarseness, hypotension and palpitations, impotence, increased heart
rate, insomnia, mental confusion, muscle cramps, muscle tremors, nausea,
nervousness, palpitations, sweating, tachycardia, unusual taste, urinary
hesitancy and retention, vertigo, vomiting, weakness, and wheezing.

[0095] In some embodiments, the dose of formoterol, glycopyrrolate or both
is less than about 75% of the standard dose. In some embodiments, the
dose of formoterol, glycopyrrolate or both is less than about 65%, 60%,
55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 15% of the standard dose. In
some embodiments, the combination is administered with a high efficiency
nebulizer. In some embodiments, the combination has a fill volume of
about 0.5 mL or less. In some embodiments, the combination is
administered in significantly less than about 3 min. In some embodiments,
the combination is administered with a conventional nebulizer. Some
embodiments provide a system or device adapted or adaptable to carry out
the method of treatment. Some embodiments provide a unit dose, which may
be used in one of the foregoing methods, comprising an effective amount
of a muscarinic antagonist and a LABA in a pharmaceutically acceptable
diluent. In some embodiments such unit dose may be contained in a kit
comprising at least one additional dose.

[0096] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of (A) a reduced dose of
glycopyrrolate; and/or (B) a reduced dose of formoterol, wherein (I) said
reduced dose of glycopyrrolate is significantly less than a standard dose
of glycopyrrolate; and (II) said reduced dose of formoterol is
significantly less than a standard dose of formoterol, and wherein said
administration produces: (a) increased magnitude and/or duration of
therapeutic effect; and (b) reduced side effects, compared to
administration, with a conventional nebulizer, of: (1) said standard dose
of glycopyrrolate alone; and (2) said standard dose of formoterol alone.
In some embodiments, the nominal dose of formoterol is significantly less
than a standard dose of formoterol and the standard dose of formoterol is
a government approved dose of formoterol administered with the same
nebulizer. In some embodiments, the nominal dose of glycopyrrolate is
significantly less than a standard dose of glycopyrrolate and the
standard dose of glycopyrrolate is a minimum effective therapeutic dose
of glycopyrrolate administered with the same nebulizer.

[0097] Some embodiments described herein provide a method of treating a
patient having COPD, comprising administering to the patient with a high
efficiency nebulizer a combination of a dose of glycopyrrolate and a dose
of formoterol, wherein said administration produces: (a) similar or
increased magnitude and/or duration of therapeutic effect; and (b)
reduced side effects, compared to administration, in a conventional
nebulizer, of: (1) the equivalent respirable dose of glycopyrrolate; 2)
the equivalent respirable dose of formoterol; and 3) the combination of
the equivalent respirable doses of glycopyrrolate and formoterol. In some
embodiments, the nominal dose of glycopyrrolate is significantly less
than a standard dose of formoterol and the standard dose of formoterol is
a government approved dose of formoterol administered with the same
nebulizer. In some embodiments, the nominal dose of glycopyrrolate is
significantly less than a standard dose of glycopyrrolate and the
standard dose of glycopyrrolate is a minimum effective therapeutic dose
of glycopyrrolate administered with the same nebulizer. In some
embodiments, the nominal dose of glycopyrrolate is significantly less
than a standard dose of formoterol and the standard dose of formoterol is
a government approved dose of formoterol administered with the same
nebulizer; and wherein the nominal dose of glycopyrrolate is
significantly less than a standard dose of glycopyrrolate and the
standard dose of glycopyrrolate is a minimum effective therapeutic dose
of glycopyrrolate administered with the same nebulizer. In some
embodiments, the duration of therapeutic effect is at least about 20 hr,
at least about 22 hr or at least about 24 hr. In some embodiments, said
administration of glycopyrrolate and formoterol results in a reduction of
one or more side effects associated with glycopyrrolate, formoterol or
both.

[0099] In some embodiments, administration of the active ingredients
permit reduction in the dose of LABA (e.g. formoterol, salmeterol,
indacaterol, etc.), LAMA (e.g. glycopyrrolate, ipratropium, etc.) or both
is less than about 75% of the standard dose. In some embodiments, the
dose of formoterol, glycopyrrolate or both is less than about 65%, 60%,
55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or 15% o of the standard dose.

[0100] In some embodiments, the combination has a fill volume of about 0.5
mL or less. In some embodiments, the combination is administered in
significantly less than about 3 min. In some embodiments, administration
of the combination produces a duration of therapeutic effect of at least
about 20 hr, at least about 22 hr or at least about 24 hr. In some
embodiments, administration of the combination produces an increased
magnitude of therapeutic effect. In some embodiments, the combination
contains about 0.25 μg to about 6 μg of R,R-formoterol or about 0.5
μg to about 8 μg of racemic formoterol. Some embodiments provide a
system or device adapted or adaptable to carry out the method of
treatment. Some embodiments provide a unit dose, which may be used in one
of the foregoing methods, comprising an effective amount of a muscarinic
antagonist and a LABA in a pharmaceutically acceptable diluent. In some
embodiments such unit dose may be contained in a kit comprising at least
one additional dose.

[0101] Methods and Systems for the Treatment of Respiratory Conditions
with HENs

[0102] The present invention provides methods and inhalation systems for
treatment or prophylaxis of a respiratory condition in a patient, such as
chronic obstructive pulmonary disease (COPD), and optionally chronic
bronchitis and/or emphysema. In some embodiments, the methods and
inhalation systems comprise administering to a patient a nominal dose of
an active pharmaceutical ingredient (API), e.g. a LABA or a muscarinic
antagonist in combination with a LABA, in an aqueous inhalation solution
with a high efficiency nebulizer inhalation device, wherein delivering
the nominal dose of the LABA or a muscarinic antagonist in combination
with a LABA to the patient with a high efficiency nebulizer provides one
or more of the following advantages: (1) an enhanced pharmacokinetic
profile as compared to administration with a conventional nebulizer; (2)
an enhanced therapeutic effect as compared to administration with a
conventional nebulizer; (3) an enhanced lung deposition evidenced by
scintigraphy or deconvolution, or derived from suitable in vitro
indicators such as enhanced RDDR, RF, GSD, and/or a MMAD values as
compared to administration with a conventional nebulizer; (4) reduced
administration times, periods, and/or volumes; (5) a reduction in adverse
side effects associated with API treatment and optionally a longer
duration of therapeutic effect; optional administration with muscarinic
antagonist and optionally a corticosteroid; or (6) an enhanced method of
treatment of acute exacerbations of a respiratory condition in a patient,
e.g. COPD.

[0103] Inhalation Therapy

[0104] An inhalation device, as used herein, refers to any device that is
capable of administering a solution to the respiratory airways of a
patient. Inhalation devices include conventional inhalation devices, such
as metered dose inhalers (MDIs), conventional nebulizers, such as jet
nebulizers, and high efficiency nebulizers, such as vibrating membrane
nebulizers.

[0105] Inhalation nebulizers, or atomizers, are also commonly used for the
treatment of COPD and other respiratory diseases Inhalation nebulizers
deliver therapeutically effective amounts of pharmaceuticals by forming
an aerosol which includes droplet sizes that can easily be inhaled. The
aerosol can be used, for example, by a patient within the bounds of an
inhalation therapy, whereby the therapeutically effective pharmaceutical
or drug reaches the patient's respiratory tract upon inhalation. Some
embodiments described herein provide for administration of a LABA or a
combination of a muscarinic antagonist (e.g. glycopyrrolate) and a LABA
(e.g. formoterol or salmeterol) with an inhalation device.

[0106] High Efficiency Nebulizer Inhalation Devices

[0107] High efficiency nebulizers are inhalation devices that are adapted
to deliver a large fraction of a loaded dose to a patient. Some high
efficiency nebulizers utilize microperforated membranes. In some
embodiments, the high efficiency nebulizer also utilizes one or more
actively or passively vibrating microperforated membranes. In some
embodiments, the high efficiency nebulizer contains one or more
oscillating membranes. In some embodiments, the high efficiency nebulizer
contains a vibrating mesh or plate with multiple apertures and optionally
a vibration generator with an aerosol mixing chamber. In some such
embodiments, the mixing chamber functions to collect (or stage) the
aerosol from the aerosol generator. In some embodiments, an inhalation
valve is also used to allow an inflow of ambient air into the mixing
chamber during an inhalation phase and is closed to prevent escape of the
aerosol from the mixing chamber during an exhalation phase. In some such
embodiments, the exhalation valve is arranged at a mouthpiece which is
removably mounted at the mixing chamber and through which the patient
inhales the aerosol from the mixing chamber. In some embodiments, the
high efficiency nebulizer contains a pulsating membrane. In some
embodiments, the high efficiency nebulizer is continuously operating. In
some embodiments the high efficiency nebulizer is breath activated.

[0108] In some embodiments, the high efficiency nebulizer contains a
vibrating microperforated membrane of tapered nozzles against a bulk
liquid, and will generate a plume of droplets without the need for
compressed gas. In these embodiments, a solution in the microperforated
membrane nebulizer is in contact with a membrane, the opposite side of
which is open to the air. The membrane is perforated by a large number of
nozzle orifices of an atomizing head. An aerosol is created when
alternating acoustic pressure in the solution is built up in the vicinity
of the membrane causing the fluid on the liquid side of the membrane to
be emitted through the nozzles as uniformly sized droplets.

[0109] Some embodiments of high efficiency nebulizers use passive nozzle
membranes and separate piezoelectric transducers that are in contact with
the solution. Another type of high efficiency nebulizer employs an active
nozzle membrane, which uses the acoustic pressure in the nebulizer to
generate very fine droplets of solution via the high frequency vibration
of the nozzle membrane.

[0110] Some high efficiency nebulizers contain a resonant system. In some
such high efficiency nebulizers, the membrane is driven by a frequency
for which the amplitude of the vibrational movement at the center of the
membrane is particularly large, resulting in a focused acoustic pressure
in the vicinity of the nozzle; the resonant frequency may be about 100
kHz. A flexible mounting is used to keep unwanted loss of vibrational
energy to the mechanical surroundings of the atomizing head to a minimum.
In some embodiments, the vibrating membrane of the high efficiency
nebulizer may be made of a nickel-palladium alloy by electroforming.

[0111] In some embodiments, the high efficiency nebulizer achieves lung
deposition of at least about 30%, at least about 35%, at least about 40%,
at least about 45%, at least about 50%, at least about 55%, at least
about 60%, about 30% to about 60%, about 30% to about 55%, about 30% to
about 50%, about 30% to about 40%, about 30% to about 90%, about 40% to
about 80%, about 50% to about 60%, or about 60% to about 70%, based on
the nominal dose of the LABA or muscarinic antagonist (e.g. LAMA) in
combination with a LABA administered to the patient.

[0112] In some embodiments, the high efficiency nebulizer provides LABA
lung deposition of at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about 60%,
about 20% to about 40%, about 25% to about 35%, about 25 to about 30%,
about 35% to about 90%, about 40% to about 80%, about 50% to about 60%,
or about 60% to about 70% based on the nominal dose of the LABA. In some
embodiments, the high efficiency nebulizer provides for one or more of
(a) or (b); and one or more of (i), (ii) or (iii): (a) a respirable dose
delivery rate (RDDR) of at least about 100 μg/min or at least about
100 μg/min to at least about 5,000 μg/min; (b) an output rate of
LABA of at least about 120 μg/min, at least about 150 μg/min, at
least about 200 μg/min or at least about 200 μg/min to at least
about 5,000 μg/min; (i) a respirable fraction (RF) of LABA of at least
about 30%, at least about 35%, at least about 40%, at least about 45%, at
least about 50%, at least about 55%, at least about 65% to at least about
75% or at least about 75% to at least about 85% respirable fraction upon
administration; (ii) a Geometric Standard Deviation (GSD) of emitted
droplet size distribution of the solution administered with a inhalation
device of about 1.1 to about 2.1, about 1.2 to about 2.0, about 1.3 to
about 1.9, less than about 2.2, about 1.4 to about 1.8, about 1.5 to
about 1.7, about 1.4, about 1.5, or about 1.6; or (iii) a Mass Median
Aerodynamic Diameter (MMAD) of droplet size of the solution emitted with
the inhalation device of about 1 μm to about 5 μm, about 2 to about
4 μm, or about 3.5 to about 4.0 μm.

[0113] Additional features of a high efficiency nebulizer with perforated
membranes are disclosed in U.S. Pat. Nos. 6,962,151, 5,152,456,
5,261,601, and 5,518,179, each of which is hereby incorporated by
reference in its entirety. Some embodiments of the high efficiency
nebulizer contain oscillating membranes. Features of these high
efficiency nebulizers are disclosed in U.S. Pat. Nos. 7,252,085;
7,059,320; 6,983,747, each of which is hereby incorporated by reference
in its entirety.

[0114] Commercial high efficiency nebulizers are available from: PAR1
(Germany) under the trade name eFlow®; Nektar Therapeutics (San
Carlos, Calif.) (now Aerogen, Ltd.) under the trade names AeroNeb® Go
and AeroNeb® Pro, and AeroNeb® Solo, Respironics (Murrysville,
Calif.) under the trade names 1-Neb®, Omron (Bannockburn, Ill.) under
the trade name Micro-Air®, and Activaero (Germany) under the trade
name Akita®. Commercial high efficiency nebulizers are also available
from Aerogen (Galaway, Ireland) utilizing the OnQ® nebulizer
technology.

[0115] Conventional Nebulizers

[0116] In some embodiments, a LABA or a combination of a muscarinic
antagonist and a LABA may be administered with a conventional nebulizer.
Conventional nebulizers include, for example jet nebulizers or ultrasonic
nebulizers. Conventional nebulizers generally utilize compressors to
generate compressed air, which breaks the liquid medication into small
breathable droplets, which form an aerosolized (atomized) mist. In some
of these embodiments, when the patient breathes in, a valve at the top
opens, which then allows air into the apparatus, thereby speeding up the
mist generation; when the patient breathes out, the top valve closes,
thereby slowing down the mist generation while simultaneously permitting
the patient to breathe out through the opening of a mouthpiece flap.

[0117] In general, conventional nebulizers are characterized by relatively
low efficiency in delivery of a API to lung tissue. Thus, a conventional
nebulizer, such as a jet nebulizer, will be generally characterized by a
respirable dose of less than 20% of the nominal dose. In some cases, the
respirable dose is also referred to as the inhaled mass, which in any
case is less than 20% of the nominal dose.

[0118] Some conventional nebulizers are disclosed in U.S. Pat. Nos.
6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000,394, 5,957,389,
5,740,966, 5,549,102, 5,461,695, 5,458,136, 5,312,046, 5,309,900,
5,280,784, and 4,496,086, each of which is hereby incorporated by
reference in its entirety.

[0119] Commercial conventional nebulizers are available from: PAR1
(Germany) under the trade names PARI LC® and PARI-Jet®; A & H
Products, Inc. (Tulsa, Okla.) under the trade name AquaTower®; Hudson
RCI (Temecula, Calif.) under the trade name AVA-NEB®; Intersurgical,
Inc. (Liverpool, N.Y.) under the trade name Cirrus®; Salter Labs
(Arvin, Calif.) under the trade name Salter 8900®; Respironics
(Murrysville, Pa.) under the trade name Sidestream®; Bunnell (Salt
Lake City, Utah) under the trade name Whisper Jett; Smiths-Medical (Hyth
Kent, UK) under the trade name Downdraft®.

[0120] Active Ingredient(s)

[0121] Muscarinic Antagonists

[0122] Acetylcholine released from cholinergic neurons in the peripheral
and central nervous systems affects many different biological processes
through interaction with two major classes of acetylcholine receptors:
the nicotinic and the muscarinic receptors.

[0123] Muscarinic acetylcholine receptors are widely distributed in
vertebrate organs where they mediate many vital functions. Three subtypes
of muscarinic acetylcholine receptors have been identified as important
in the lung, M1, M2, and M3, each with its unique pharmacological
properties and a product of a distinct gene. These three subtypes are
also located in organs other than the lung.

[0124] In the lung, M3 muscarinic receptors mediate smooth muscle
contraction. Stimulation of M3 muscarinic receptors activate the enzyme
phospholipase C via binding of the stimulatory G protein Gq/11 (Gs),
leading to liberation of phosphatidyl inositol-4,5-bisphosphate,
resulting in phosphorylation of contractile proteins and bronchial
constriction. M3 muscarinic receptors are also found on pulmonary
submucosal glands. Stimulation of this population of M3 muscarinic
receptors results in mucus secretion. M2 muscarinic receptors make up
approximately 50-80% of the cholinergic receptor population on airway
smooth muscles. Under normal physiological conditions, M2 muscarinic
receptors provide tight control of acetylcholine release from
parasympathetic nerves. M1 muscarinic receptors are found in the
pulmonary parasympathetic ganglia where they function to enhance
neurotransmission.

[0125] Muscarinic acetylcholine receptor dysfunction in the lungs has been
noted in a variety of different pathophysiological states. In asthma and
COPD patients, inflammatory conditions lead to loss of inhibitory M2 and
M3 muscarinic acetylcholine autoreceptor function on parasympathetic
nerves supplying the pulmonary smooth muscle, causing an increased
release of acetylcholine. This dysfunction in muscarinic receptors
results in airway hyperreactivity and hyperresponsiveness.

[0126] Muscarinic acetylcholine receptor antagonist agents, or muscarinic
antagonists, have the ability to inhibit the action of the
neurotransmitter acetylcholine by blocking its interaction with
muscarinic cholinergic receptors in general, and its interaction with
specific muscarinic receptor subtypes in particular. Muscarinic
antagonists thereby prevent the effects resulting from the passage of
unnecessary impulses through the parasympathetic nerves mediated by
increased stimulation in patients with dysfunctional receptors, resulting
in, among other physiological effects, relaxation of smooth muscles in
the lung.

[0127] Aclidinium,

[0128] ((3R-3-{[hydroxydi(thiophen-2-yl)acetyl]oxy}-1-(3-phenoxypropyl)-1--
azoniabicyclo[2.2.2]octane bromide), is a specific long-acting muscarinic
receptor antagonist. Aclidinium is in development for use as an
anticholinergic agent. Clinically, aclidinium has been tested in a dry
powder inhaled format.

[0129] In some embodiments of the present invention, the muscarinic
antagonist is aclidinium and is administered at a nominal dosage of 100
μg/dose to about 5 mg/dose, about 50 μg/dose to about 2 mg/dose or
about 50 μg/dose to about 1 mg per dose. In some embodiments,
aclidinium is given in 100 μg, 200 μg, 300 μg, 400 μg, 500
μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1,000 μg doses.

[0130] The process of making aclidinium is known by a person of ordinary
skill in the art. Aclidinium can be made by a number of known methods
including those described in U.S. Pat. No. 6,750,226, which is
incorporated herein by reference in its entirety, and which sets forth
several structurally related muscarinic antagonists. Additional examples
of muscarinic antagonists are set forth in U.S. Pat. Nos. 7,312,231 and
7,208,501, each of which is incorporated herein by reference in its
entirety.

[0131] Trospium

[0132] (endo-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]oca-
tane-8,1'-pyrrolidinium]chloride benzilate), is a specific long-acting
muscarinic receptor antagonist. Trospium has been known for many years to
be an effective anticholinergic agent. Clinically, trospium has been used
in several indications and been delivered by a number of different
routes. Currently, trospium is used as a urinary antispasmotic and is
sold under the brand name Sanctura®.

[0133] In some embodiments of the present invention, the muscarinic
antagonist is trospium and is administered at a nominal dosage of 10
μg/dose to about 5 mg/dose, about 10 μg/dose to about 2 mg/dose or
about 50 μg/dose to about 1 mg per dose. In some embodiments, trospium
is given in 10 μg, 50 μg, 100 μg, 200 μg, 300 μg, 400
μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1,000
μg doses.

[0134] The process of making trospium is known by a person of ordinary
skill in the art. Trospium can be made by a number of known methods
including those described in U.S. Pat. No. 3,480,626, which is
incorporated herein by reference in its entirety.

[0135] Glycopyrrolate,

[0136] 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium,
is a specific long-acting muscarinic receptor antagonist. Glycopyrrolate
has been known for many years to be an effective anticholinergic agent.
Clinically, glycopyrrolate has been used in several indications and been
delivered by a number of different routes. Currently, glycopyrrolate is
used as an injectable compound to reduce gastric acid secretions during
anesthesia and also as an oral product for treating gastric ulcers.

[0137] In some embodiments of the present invention, the muscarinic
antagonist is glycopyrrolate and is administered at a nominal dosage of
100 μg/dose to about 5 mg/dose, about 200 μg/dose to about 2
mg/dose or about 250 μg/dose to about 1 mg per dose.

[0138] The process of making glycopyrrolate is known by a person of
ordinary skill in the art. Glycopyrrolate can be made as follows. First,
alpha-phenylcyclopentaneglycolic acid is esterified by refluxing with
methanol in the presence of hydrochloric acid and the resulting ester is
transesterified with 1-methyl-3-pyrrolidinol using sodium as a catalyst;
the transester is then reacted with methyl bromide to give
glycopyrrolate. U.S. Pat. No. 6,433,003, which describes this process in
more detail, is hereby incorporated by reference in its entirety.

[0139] Glycopyrrolate for injectable and oral administration is readily
commercially available. Injectable glycopyrrolate in commercial
administrations are sold by: Baxter Healthcare, Inc. (Deerfiled, Ill.)
under the trade name Robinul and by Luitpold Pharmaceuticals, Inc.
(Shirley, N.Y.) under the generic name glycopyrrolate. Oral
glycopyrrolate is commercially available under the generic name
glycopyrrolate from Corepharma, LLC (Middlesex, N.J.) and Kali
Laboratories, Inc. (Somerset, N.J.), and is available from Sciele Pharma,
Inc. (Atlanta, Ga.) under the trade names Robinul and Robinul Forte.

[0140] Muscarinic antagonists can be long-acting or short-acting.
Long-acting muscarinic antagonists have a therapeutic effect lasting
greater than about 6 hours. Short-acting muscarinic antagonists have a
duration of therapeutic effect of less than about 6 hours. Long-acting
muscarinic antagonists include, but are not limited to, glycopyrrolate,
tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK656398, BEA 2180,
or a pharmaceutical acceptable derivative, salt, enantiomer,
diastereomer, or racemic mixtures thereof.

[0144] The stimulation of beta 2-adrenergic receptors stimulates adenylate
cyclase, resulting in an increased level of the second messenger cAMP
that in turn leads to decreased intracellular calcium concentration and
consequently smooth muscle relaxation. Stimulation of certain beta
2-adrenergic receptors in particular causes hydrolysis of
polyphosphoinositides and mobilization of intracellular calcium which
results in a variety of calcium mediated responses such as smooth muscle
contraction. Consequently, inhibition of this receptor activation
prevents the intracellular calcium increase and leads to smooth muscle
relaxation.

[0145] Beta 2-agonists (i.e. beta 2-adrenoreceptor agonists) can be
long-acting or short-acting. Long-acting beta 2-agonists (LABAs) have a
therapeutic effect lasting greater than about 6 hours. Short-acting beta
2-agonists (SABAs) have a duration of therapeutic effect of less than
about 6 hours.

[0147] Formoterol is a long-acting beta 2-agonist compound. The process of
making formoterol is known by one of skill in the art. Formoterol is
derived from adrenaline and is used as a beta 2-agonist in inhalation
therapy of respiratory diseases. Formoterol has been formulated as a dry
powder and administered via devices such as the Turbuhaler® and the
Aerolizer®.

[0148] Formoterol is also available as a tablet and a dry syrup in certain
areas of the world (e.g., Atock®, marketed by Yamanouchi
Pharmaceutical Co. Ltd., Japan). Formoterol administrations are also
available in other areas (e.g., Europe and U.S.) for propellant-based
metered dose inhalers and dry powder inhalers (e.g., Turbuhaler®,
Aerolizer® and Foradil Aerolizer®). None of these administrations
are water based solutions. In some embodiments, the nebulized solution is
a solution of formoterol and is delivered as a nominal dose of about 0.25
μg to about 20 μg per dose, about 0.25 μg to about 15 μg per
dose, 0.25 μg to about 10 μg per dose, 0.25 μg to about 8 μg
per dose, 0.25 μg to about 6 μg per dose, 0.25 μg to about 6
μg per dose, 0.25 μg to about 4 μg per dose, 0.25 μg to about
2 μg per dose, 0.5 μg to about 20 μg per dose, about 0.5 μg
to about 15 μg per dose, about 0.5 μg to about 10 μg per dose,
about 0.5 μg to about 8 μg per dose, about 0.5 μg to about 6
μg per dose, about 0.5 μg to about 6 μg per dose, about 0.5
μg to about 4 μg per dose, about 0.5 μg to about 2 μg per
dose, about 1 μg to about 20 μg per dose, about 1 μg to about 15
μg per dose, about 1 μg to about 10 μg per dose, about 1 μg
to about 8 μg per dose, about 1 μg to about 6 μg per dose, about
1 μg to about 6 μg per dose, about 1 μg to about 4 μg per
dose or about 1 μg to about 2 μg per dose. In some embodiments, the
nebulized solution is a solution of arformoterol and is delivered as a
nominal dose of about 0.25 μg to about 30 μg per dose, about 0.25
μg to about 25 μg per dose, 0.25 μg to about 15 μg per dose,
0.25 μg to about 8 μg per dose, about 0.25 μg to about 5 μg
per dose, about 0.25 μg to about 4 μg per dose, 0.25 μg to about
3 μg per dose, 0.25 μg to about 2 μg per dose, 0.25 μg to
about 1 μg per dose, about 0.5 μg to about 30 μg per dose, about
0.5 μg to about 25 μg per dose, 0.5 μg to about 15 μg per
dose, 0.5 μg to about 8 μg per dose, about 0.5 μg to about 5
μg per dose, about 0.5 μg to about 4 μg per dose, 0.5 μg to
about 3 μg per dose, 0.5 μg to about 2 μg per dose, 0.5 μg to
about 1 μg per dose, about 0.8 μg to about 30 μg per dose, about
0.8 μg to about 25 μg per dose, 0.8 μg to about 15 μg per
dose, 0.8 μg to about 8 μg per dose, about 0.8 μg to about 5
μg per dose, about 0.8 μg to about 4 μg per dose, 0.8 μg to
about 3 μg per dose, 0.8 μg to about 2 μg per dose, 0.8 μg to
about 1 μg per dose, about 1 μg to about 30 μg per dose, about 1
μg to about 25 μg per dose, 1 μg to about 15 μg per dose, 1
μg to about 8 μg per dose, about 1 μg to about 5 μg per dose,
about 1 μg to about 4 μg per dose, 1 μg to about 3 μg per
dose, 1 μg to about 2 μg per dose, about 2 μg to about 30 μg
per dose, about 2 μg to about 25 μg per dose, 2 μg to about 15
μg per dose, 2 μg to about 8 μg per dose, about 2 μg to about
5 μg per dose, about 2 μg to about 4 μg per dose or about 2
μg to about 3 μg per dose.

[0149] Commercial administrations of arformoterol tartrate
(R,R-formoterol) are sold by Sepracor, Inc. (Marlborough, Mass.) under
the trade name Brovana®. Formoterol fumarate is sold by several
companies including AstraZeneca, Inc. (London, England) under the trade
name Oxis®, Novartis International AG (Basel, Switzerland) under the
trade names Foradil® and Certihaler®, and Dey, L.P. (Napa,
Calif.) under the trade name Perforomist®. As used herein,
"formoterol" (unless further qualified) refers generically to all forms
of formoterol, such as arformoterol, racemic formoterol (mixture of R,
R-formoterol and S,S-foroterol), or a pharmaceutically acceptable salt
thereof "Arformoterol" refers to enantiomerically pure (at least 90%)
R,R-formoterol. "Racemic formoterol" (or formoterol racemate) refers to
an approximately 50:50 mixture of R,R-formoterol and S,S-formoterol.

[0150] Salmeterol is a long-acting beta 2-agonist compound. The process
for making salmeterol is known by a person of ordinary skill in the art
and is described in U.S. Pat. No. 4,992,474, which is hereby incorporated
by reference. Commercial administrations of salmeterol are sold by
GlaxoSmithKline, Inc. (Triangle Park, N.C.) under the trade names
Advair® and Serevent®. In some embodiments, the nebulized LABA is
salmeterol and is administered as a nominal dose of about 1 μg to
about 200 μg per dose, about 1 μg to about 150 μg per dose,
about 1 μg to about 100 μg per dose, about 1 μg to about 50
μg per dose, about 1 μg to about 35 μg per dose, about 1 μg
to about 30 μg per dose, about 1 μg to about 25 μg per dose,
about 1 μg to about 20 μg per dose, about 1 μg to about 15 μg
per dose, about 1 μg to about 10 μg per dose, about 5 μg to
about 200 μg per dose, about 5 μg to about 150 μg per dose,
about 5 μg to about 100 μg per dose, about 5 μg to about 50
μg per dose, about 5 μg to about 35 μg per dose, about 5 μg
to about 30 μg per dose, about 5 μg to about 25 μg per dose,
about 5 μg to about 20 μg per dose, about 5 μg to about 15 μg
per dose, about 5 μg to about 10 μg per dose, about 10 μg to
about 200 μg per dose, about 10 μg to about 150 μg per dose,
about 10 μg to about 100 μg per dose, about 10 μg to about 50
μg per dose, about 10 μg to about 35 μg per dose, about 10 μg
to about 30 μg per dose, about 10 μg to about 25 μg per dose,
about 10 μg to about 20 μg per dose, about 10 μg to about 15
μg per dose, about 20 μg to about 200 μg per dose, about 20
μg to about 150 μg per dose, about 20 μg to about 100 μg per
dose, about 20 μg to about 50 μg per dose, about 10 μg to about
45 μg per dose, about 10 μg to about 40 μg per dose, about 10
μg to about 35 μg per dose, about 10 μg to about 30 μg per
dose, about 10 μg to about 25 μg per dose, about 10 μg to about
20 μg per dose or about 10 μg to about 15 μg per dose. In some
embodiments, the LABA is R-salmeterol administered within one of the
immediately foregoing ranges set forth for salmeterol.

[0153] The present invention relates to methods and inhalation systems for
the use of inhalation solutions in an inhalation device for the treatment
or prophylaxis of a respiratory condition in a patient, such as COPD,
chronic bronchitis, or emphysema. In some embodiments, the methods and
inhalation systems comprise administering to the patient a nominal dose
of one or more API, for example a LABA or a muscarinic antagonist in
combination with a LABA, in an aqueous inhalation solution with an
inhalation device, e.g. a high efficiency nebulizer or a conventional
nebulizer a high efficiency nebulizer, conventional nebulizer, and
optionally a conventional inhalation device.

[0154] In some embodiments, the aqueous inhalation solution is
administered with an inhalation device, e.g. high efficiency nebulizer,
at a fill volume of 0.5 mL or less, at least about 0.5 mL to about 1.5
mL, at least about 0.25 mL or less, at least about 0.5 mL to about 1.5
mL, at least about 1.5 mL, or at least about 2.0 mL. In some embodiments,
the aqueous inhalation solution is administered with an inhalation
device, e.g. high efficiency nebulizer, at a fill volume of at least
about 0.25 mL to about 2.0 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL
to about 1.0 mL, about 0.5 mL or less, about 1 mL or less, about 1.5 mL
or less, or about 2.0 mL or less. In some embodiments, the aqueous
inhalation solution is administered with an inhalation device, e.g. a
high efficiency nebulizer, which provides for a residual volume of a
muscarinic antagonist in combination with a LABA after administration of
the muscarinic antagonist in combination with a LABA of less than about
10%, less than about 5%, or less than about 3% of the nominal dose.

[0155] In some embodiments, the aqueous inhalation solution is
administered in about 0.25 to about 10 minutes, about 0.50 to about 8
minutes, less than about 8, less than about 7, less than about 6, less
than about 5, less than about 4, less than about 3, less than about 2, or
less than about 1.5 minutes. In some embodiments, the aqueous inhalation
solution is administered in about 3 minutes or less.

[0156] In some embodiments, the nominal dose administered with the high
efficiency nebulizer is a LABA or a muscarinic antagonist in combination
with a LABA that is substantially free of preservative, such as benzyl
alcohol. In some embodiments, the nominal dose of LABA or muscarinic
antagonist (e.g. LAMA) in combination with a LABA is in an inhalation
solution that further comprises at least one excipient or active adjunct.
In some embodiments, the excipient or adjunct is a member of the group
consisting of organic acid (such as a low molecular weight organic acid
like citric acid or ascorbic acid), an antioxidant (such as EDTA), an
osmolarity adjusting agent (such as a salt like sodium chloride) or a pH
buffer.

[0157] In some embodiments, the inhalation solution comprising the LABA or
muscarinic antagonist (e.g. LAMA) in combination with a LABA further
comprises a corticosteroid, such as fluticasone, mometasone,
beclomethasone, triamcinolone, fluniolide, ciclesonide, or budesonide. In
some embodiments, the inhalation solution further comprises an excipient
or active adjunct. Examples of excipients and active adjuncts include an
organic acid (e.g. citric acid, ascorbic acid or a combination of both),
pilocarpine, cevimeline or carboxymethylcellulose, or a mucolytic
compound.

[0158] High Concentration Inhalation Solutions

[0159] In some embodiments, the aqueous inhalation solution administered
with an inhalation device, e.g. a metered dose inhaler (MDI),
conventional nebulizer, or high efficiency nebulizer, contains a high
concentration of muscarinic antagonist and LABA. The high concentration
of muscarinic antagonist and LABA provides certain advantages as compared
to a lower concentration solution. For example, in some embodiments, a
high concentration solution may be administered less frequently than a
low concentration solution. While not wishing to be bound by theory, it
is considered that the high concentration solution allows for gradual
uptake of the muscarinic antagonist, which provides a longer duration of
action than the lower concentration solution.

[0160] In some embodiments, the high concentration aqueous inhalation
solution of API, for example glycopyrrolate, results in a dosing regimen
aimed at achieving once-a-day dosing. In some embodiments, the methods
and systems employ a high concentration aqueous inhalation solution of
muscarinic antagonist, for example glycopyrrolate, containing at least
about 0.25 mg/mL to about 50 mg/mL, about 0.25 mg/mL to about 20 mg/mL,
about 0.25 mg/mL to about 10 mg/mL, about 0.5 mg/mL to about 50 mg/mL,
about 0.5 mg/mL to about 20 mg/mL, about 0.5 mg/mL to about 10 mg/mL, at
least about 0.5 mg/mL, at least about 1.0 mg/mL, or at least about 1.5
mg/mL, at least about 2.0 mg/mL, at least about 5 mg/mL, at least about
10 mg/mL, at least about 20 mg/mL or at least about 25 mg/mL. In some
embodiments, the concentration of glycopyrrolate is about 0.05 mg/mL to
about 50 mg/mL, about 0.05 mg/mL to about 20 mg/mL, about 0.05 mg/mL to
about 10 mg/mL, about 0.10 mg/mL to about 50 mg/mL, about 0.10 mg/mL to
about 20 mg/mL, about 0.10 mg/mL to about 10 mg/mL, about 0.2 mg/mL to
about 50 mg/mL, about 0.2 mg/mL to about 20 mg/mL, about 0.2 mg/mL to
about 2 mg/mL.

[0161] In some embodiments, the muscarinic antagonist, for example
glycopyrrolate, nominal dose of aqueous inhalation solution is about 0.05
mg to about 50 mg, about 0.05 mg to about 20 mg, about 0.05 mg to about
10 mg, about 0.05 mg to about 5 mg, about 0.05 mg to about 3 mg, 0.25 mg
to about 50 mg, about 0.25 mg to about 20 mg, about 0.25 mg to about 10
mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 3 mg, 0.2 mg to
about 2 mg, about 0.25 mg to about 1.5 mg, about 0.25 to about 1 mg, at
least about 0.25 mg, at least about 0.5 mg, at least about 1.0 mg, at
least about 1.5 mg, or at least about 2.0 mg.

[0162] In some embodiments, the high concentration aqueous inhalation
solution has a fill volume of about 0.5 mL to about 1.5 mL, about 0.5 mL
to about 1.0 mL, about 0.5 mL or less, about 1 mL or less, or about 1.5
mL. In some embodiments, the aqueous inhalation solution is administered
in about 0.25 to about 10 minutes, about 0.50 to about 8 minutes, less
than about 8, less than about 7, less than about 6, less than about 5,
less than about 4, less than about 3, less than about 2, or less than
about 1.5 minutes. In some embodiments, the aqueous inhalation solution
is administered in about 3 minutes or less.

[0163] In some embodiments, the high concentration nominal dose of the
muscarinic antagonist administered with an inhalation device provides for
a greater duration of therapeutic effect compared to administration of a
lower concentration or higher volume of substantially the same nominal
dose of muscarinic antagonist. In some embodiments, the nominal dose of
muscarinic antagonist administered with an inhalation device provides for
a shorter time to onset of therapeutic effect compared to administration
of a lower concentration or higher volume of substantially the same
nominal dose of muscarinic antagonist. In some embodiments, the nominal
dose of muscarinic antagonist administered with an inhalation device
provides for a shorter time to maximum therapeutic effect compared to
administration of a lower concentration or higher volume of substantially
the same nominal dose of muscarinic antagonist.

[0164] Characterization of Inhalation Devices

[0165] The efficiency of a particular inhalation device can be measured by
many different ways, including an analysis of pharmacokinetic properties,
measurement of lung deposition percentage, measurement of respirable dose
delivery rates (RDDR), a determination of output rates, respirable
fraction (RF), geometric standard deviation values (GSD), and mass median
aerodynamic diameter values (MMAD) among others.

[0166] A person skilled in the art is knowledgeable of methods and systems
for examining a particular inhalation device. One such system consists of
a computer and a hollow cylinder in a pump with a connecting piece to
which an inhalation device is to be connected. In the pump there is a
piston rod, which extends out of the hollow cylinder. A linear drive unit
can be activated in such a manner that one or more breathing patterns
will be simulated on the connecting piece of the pump. In order to be
able to carry out the evaluation of the inhalation device, the computer
is connected in an advantageous configuration with a data transmitter.
With the aid of the data transmitter, the computer can be connected with
another computer with specific data banks, in order to exchange the data
of breathing patterns. In this manner, a breathing pattern library which
is as representative as possible can be very rapidly formed. U.S. Pat.
No. 6,106,479 discloses this method for examining an inhalation device in
more detail, and is hereby incorporated by reference in its entirety.

[0167] Pharmacokinetic Profile

[0168] Pharmacokinetics is concerned with the uptake, distribution,
metabolism and excretion of a drug substance. A pharmacokinetic profile
comprises one or more biological measurements designed to measure the
absorption, distribution, metabolism and excretion of a drug substance.
One way of visualizing a pharmacokinetic profile is by means of a blood
plasma concentration curve, which is a graph depicting mean active
ingredient blood plasma concentration on the Y-axis and time (usually in
hours) on the X-axis. Some pharmacokinetic parameters that may be
visualized by means of a blood plasma concentration curve include:

[0169] AUClast: The area under the curve from time zero to time of
last measurable concentration.

[0170] AUC.sub.(0-∞): The total area under the curve.

[0171] Cmax: The maximum plasma concentration in a patient.

[0172] Tmax: The time to reach maximum plasma concentration in a
patient

[0173] An enhanced pharmacokinetic profile in a patient can be indicated
by increased AUClast AUC.sub.(0-∞), Cmax, or a decreased
Tmax. Enhanced levels of a pharmaceutical agent in the blood plasma
of a patient may result in or more improved symptoms of an airway
respiratory condition, e.g. COPD.

[0174] In some embodiments, a method or system described herein provides
at least about a 1.5-, 1.8- or even a two-fold enhancement in
pharmacokinetic profile, meaning that administration of an active
pharmaceutical ingredient ("API"--a LABA or a muscarinic antagonist in
combination with a LABA) with a high efficiency nebulizer provides at
least about a two-fold increase in one or more of AUClast,
AUC.sub.(0-∞), or Cmax as compared to the same or lower
nominal dose of API administered with a conventional nebulizer.

[0175] In some embodiments, a method or system described herein provides
at least about a two-fold enhancement in pharmacokinetic profile, meaning
that administration of an active pharmaceutical ingredient ("API"--e.g. a
LABA or a muscarinic antagonist in combination with a LABA) with a high
efficiency nebulizer provides a comparable AUClast,
AUC.sub.(0-∞), or Cmax as compared to the same or lower
nominal dose of API administered with a conventional nebulizer.

[0176] Enhanced Therapeutic Effect

[0177] The assessment of therapeutic effect is known to those skilled in
the art, such as pulmonologists trained to recognized the distinctions
between various types of respiratory illnesses, including chronic
obstructive pulmonary disease ("COPD") and asthma. Assessment of efficacy
may be carried out by various methods known to the person skilled in the
art, and may include both objective and subjective (patient-generated)
measures of efficacy. Objective measures of efficacy can be obtained
inter alia by spirometry; and subjective measures of efficacy can be
obtained for example by employing one or more patient symptom
questionnaires or surveys. In some embodiments, the methods and systems
herein are for treatment of COPD, and thus such embodiments are discussed
in further detail below. It is considered that embodiments of the methods
and symptoms described herein (including those employing administration
of a LABA or a muscarinic antagonist in combination with a LABA,
optionally with a high efficiency nebulizer or at a high concentration)
will provide superior efficacy in treatment of COPD as compared to
treatment with conventional methods (such as those in which muscarinic
antagonist or LABA is administered as a monotherapy, with a conventional
nebulizer and/or at a relatively low concentration).

[0178] COPD Efficacy Assessment

[0179] COPD is a progressive, chronic disease of the airways,
characterized by chronic inflammation and destruction of the airways and
lung parenchyma, resulting in airflow obstruction. Thus, efficacy in the
treatment of COPD refers to the ability to restore airflow to the
patient. In some cases, especially in older and immune-compromised
patients, COPD can be further characterized by exacerbations--acute,
often pathogen--or allergen-induced, degradation of airflow. There are
several indicators (endpoints) of efficacy in the treatment of COPD. Some
efficacy endpoints that are used in COPD studies are set forth below. It
is considered that a muscarinic antagonist in combination with a LABA
will demonstrate efficacy in one or more of these tests. In particular,
it is considered that in some embodiments a nominal dose of a muscarinic
antagonist in combination with a LABA, administered with a high
efficiency nebulizer, will out-perform substantially the same or higher
nominal dose of muscarinic antagonist in combination with a LABA
administered with a conventional nebulizer, as determined by one or more
of these endpoints. In some embodiments, it is considered that a
combination of a muscarinic antagonist with a LABA will out-perform the
muscarinic antagonist as monotherapy, and/or the LABA as a monotherapy,
as determined by one or more of these endpoints.

[0180] Pulmonary Function Tests:

[0181] Pulmonary function testing by spirometry is a useful way to assess
airflow obstruction and, therefore, is a useful way to assess the
efficacy of COPD treatment as well as to compare the relative merits of
different COPD treatments--e.g. administration of different dosages of
active pharmaceutical ingredient ("API"), administration of substantially
the same dosages of API with different delivery devices, or
administration of different dosages of API with different delivery
devices. Forced expiratory volume in one second (FEV1) obtained from
typical spirometry is commonly used as an efficacy endpoint because
FEV1 is a reflection of the extent of airway obstruction. Spirometry
is also well-standardized, is easy to perform and provides consistent,
reproducible results across different pulmonary function laboratories.
Air-trapping and hyperinflation are common features in COPD, particularly
in emphysematous-type, and are reflected in parameters of lung function
testing, such as an elevation in the residual volume to total lung
capacity ratio (RV/TLC). Hyperinflation is believed to be responsible, at
least in part, for the sense of dyspnea.

[0182] Exercise Capacity:

[0183] Reduced capacity for exercise is a typical consequence of airflow
obstruction in COPD patients, particularly because of dynamic
hyperinflation occurring during exercise. Assessment of exercise capacity
by treadmill or cycle ergometry combined with lung volume assessment is
in some cases a tool to assess efficacy of a COPD drug. Alternative
assessments of exercise capacity, such as the Six Minute Walk or Shuttle
Walk, can also be used in some cases. The characteristics, including the
limitations, of these tests will be known to those skilled in the art.

[0184] Outcome Measures can also be used, alone or preferably in
combination with one or more objective tests, to determine efficacy of
COPD therapy.

[0185] Symptom Scores:

[0186] Symptom scores determined by asking patients to evaluate specific
symptoms on a categorical, visual or numerical scale can be a simple way
to assess efficacy of a drug based on the patient's own assessment of
health status. Symptom scores can be valuable for assessing efficacy of a
drug specifically aimed at relieving a symptom. In clinical programs
aimed at other aspects of COPD, patient-reported symptom scores can be
useful in assessing secondary effects of the therapy and may provide
important additional evidence of efficacy. The characteristics, including
the limitations, of these tests will be known to those skilled in the
art.

[0187] Activity Scales: Activity scales such as the Medical Research
Council dyspnea score, the Borg Scale, and the Mahler Baseline Dyspnea
Index/Transitional Dyspnea Index, can be used in some cases as supportive
evidence of efficacy. These scales are relatively simple to administer.
The characteristics, including the limitations, of these tests will be
known to those skilled in the art.

[0188] Health-related, quality-of-life instruments: Health-related
quality-of-life instruments, such as the St. George's Respiratory
Questionnaire and the Chronic Respiratory Questionnaire, are designed to
systematically assess many different aspects of the effect of COPD on a
patient's life. These instruments can be used to assess efficacy of a
drug. These instruments are multidimensional and assess various effects
of the disease on a patient's life and health status. The
characteristics, including the limitations, of these tests will be known
to those skilled in the art.

[0189] Further information regarding testing drugs for efficacy in the
treatment of COPD can be found in the United States Food and Drug
Administration's guidance document entitled: "Guidance for Industry:
Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment,"
November, 2007, which is available from
www.fda.gov/cder/guidance/index.htm.

[0190] A LABA or a muscarinic antagonist in combination with a LABA is
said to have a therapeutic effect in the treatment of COPD when it causes
an increase in one or more measures of pulmonary function to a
predetermined percentage above baseline. In some embodiments, the
predetermined percentage above baseline is about 5%, about 10%, about
15%, about 20%, or about 25%. In some specific embodiments, a LABA or a
muscarinic antagonist in combination with a LABA will be considered to
have a therapeutic effect when it raises one or more of the
above-mentioned spirometry measurements (e.g. FEV1) at least about
15% above baseline. In some embodiments, the baseline is considered the
spirometry measurement immediately prior to administration of the
nebulized combination; in some embodiments, the baseline is considered
the spirometry measurement obtained at substantially the same time of day
upon administration of placebo.

[0191] Spirometry is the measurement of respiration, which is generally
conducted by a physician with the aid of a spirometer. Spirometers
measure inspired and expired airflow for the purpose of assessing
pulmonary ventilatory function. Spirometry is the most common pulmonary
function test measuring lung function. Typical spirometers display
volume-time curves (showing volume on the Y-axis and time, usually in
seconds, on the X-axis) and optionally flow-volume curves (showing rate
of flow on the Y-axis and the total volume inspired/expired on the
X-axis). U.S. Pat. No. 7,291,115 discloses a spirometer and method to
measure the ventilatory function by spirometry, and is hereby
incorporated by reference in its entirety. Methods of using a spirometer
are familiar to those skilled in the art.

[0192] Relevant parameters measured by spirometers include:

[0193] FEV1 (or FEV1): Forced Expiratory Volume in 1 Second, which is
the maximum volume of air exhaled during the first second of maximum
effort from a maximum inhalation. It is expressed in liters and in
percentage of the patient's reference value from baseline. It becomes
altered in cases of bronchial obstruction and it is fundamental for
diagnosing and monitoring obstructive diseases, e.g. COPD.

[0194] Change in FEV1: Change in FEV1 may be calculated as the difference
between the FEV1 value measured after dosing and the FEV1 measured
immediately prior to dosing. Change in FEV1 may also be measured in
reference to a placebo. These values may be expressed in absolute terms
or in terms of percent change from baseline or placebo.

[0195] FEV1 AUC (or FEV1 AUC): This is the area between the FEV1
measurements vs. time curve over a time course. In some embodiments, the
time course is a predetermined period, such as 0-6 hr., 0-12 hr., 0-18
hr., 0-24 hr., 0-30 hr., or 0-36 hr.

[0196] Trough FEV1 (or Trough FEV1): This is the FEV1 value measured
just prior to administration of the drug. In some cases, the trough FEV1
is obtained in the morning, just prior to administration of the drug. In
some embodiments, the change in trough FEV1 is the difference between the
trough FEV1 for the drug and the trough FEV1 for a placebo, after a
period of time. In some embodiments, the change in the trough FEV1 is
measured over a predetermined time course, such as 1 wk, 2 wk, 4 wk or 12
wk.

[0197] FVC: Forced Vital Capacity, which is the maximal volume of air
exhaled with maximal effort from a position of maximal inhalation. It is
expressed in liters and in percentage of a patient's reference value from
baseline.

[0198] FEV1/FVC: The quotient of FEV1 and FVC. Normal values of FEV1/FVC
are greater than 0.75.

[0199] PEF: Peak Expiratory Flow, which is the highest expiratory flow
achieved with maximal effort from a position of maximal inspiration. This
is essentially the speed of the air moving out of the lungs of a patient
at the beginning of expiration. It is expressed in liters/second or in
liters/minute.

[0200] FEF25-75: Forced Expiratory Flow from 25% to 75% on the
flow-volume curve, which is the average flow (or speed) of air coming out
of the lung during the middle portion of expiration.

[0201] FEF25-50: Forced Expiratory Flow from 25% to 50% on the
flow-volume curve, which is another measure of the average flow (or
speed) of air coming out of the lung during the middle portion of
expiration.

[0202] FIF25-75: Forced Inspiratory Flow from 25% to 75% on the
flow-volume curve, which is the average flow (or speed) of air entering
the lung during the middle portion of inspiration.

[0203] FIF25-50: Forced Inspiratory Flow from 25% to 75% on the
flow-volume curve, which is another measure of the average flow (or
speed) of air entering the lung during the middle portion of inspiration.

[0204] An enhanced therapeutic effect can include an increased magnitude
of therapeutic effect, an enhanced duration of therapeutic effect, an
enhanced time to onset of therapeutic effect, a shorter time to maximum
therapeutic effect or a greater magnitude of therapeutic effect. In some
embodiments described herein, an enhanced therapeutic effect relates to
the increased ability of a pharmaceutical agent to relieve the symptoms
of an airway respiratory disorder, e.g. COPD. Thus, an enhanced
therapeutic effect may be determined by comparing values of change in
FEV1 (i.e. change in FEV1 from baseline or compared to a
placebo), % change in FEV1 (i.e. percent change in FEV1 from
baseline or compared to placebo), FEV1 AUC, trough FEV1,
FEV1/FVC, PEF, FEF25-75, FEF25-50, FIF25-75,
FIF25-50 obtained from a patient or patient population in one
therapeutic milieu versus another anther therapeutic milieu. For example,
an enhanced therapeutic effect may be determined by comparing FEV1
values for a patient or patient population treated with a muscarinic
antagonist administered with a high efficiency nebulizer against the same
drug administered with a conventional nebulizer. In another example, an
enhanced therapeutic effect may be determined by comparing FEV1
values for a patient or patient population treated with a muscarinic
antagonist administered at a high concentration against the same drug
administered at a low concentration. In some cases, an enhanced
therapeutic effect may be determined by comparing FEV1 values for a
patient or patient population treated with a muscarinic antagonist
administered with a high efficiency nebulizer against a muscarinic
antagonist alone administered with a conventional nebulizer. In another
example, an enhanced therapeutic effect may be determined by comparing
FEV1 values for a patient or patient population treated with a
muscarinic antagonist administered at a high concentration against a
muscarinic antagonist alone administered at a low concentration. In some
embodiments, the enhanced therapeutic effect is an increased magnitude of
therapeutic effect. In some embodiments, the increased magnitude of
therapeutic effect is an increase in the peak FEV1 obtained with a
high efficiency nebulizer versus the peak FEV1 obtained with a
conventional nebulizer. In some embodiments, the peak FEV1 obtained
with a high efficiency nebulizer is at least about 10%, 15%, 20%, or 30%
above that obtained with a conventional nebulizer. In some embodiments,
the peak FEV1 obtained with a high efficiency nebulizer is at least
about 25 mL, 50 mL, or 100 mL above that obtained with a conventional
nebulizer. In some embodiments, the increased magnitude of therapeutic
effect is an increase in the mean FEV1 obtained with a high
efficiency nebulizer versus the mean FEV1 obtained with a
conventional nebulizer. In some embodiments, the mean FEV1 obtained
with a high efficiency nebulizer is at least about 5%, 10%, or 15% above
that obtained with a conventional nebulizer. In some embodiments, the
mean FEV1 obtained with a high efficiency nebulizer is at least
about 50 mL, 100 mL, or 150 mL above that obtained with a conventional
nebulizer. In some embodiments, the increased magnitude of therapeutic
effect is an increase in the AUC for the FEV1 versus time curve
obtained with a high efficiency nebulizer versus the AUC for the
FEV1 versus time curve obtained with a conventional nebulizer. In
some embodiments, the increase in AUC of the FEV1 versus time curve
obtained with a high efficiency nebulizer is at least about 50%, 75% or
100% above that obtained with a conventional nebulizer.

[0205] In some embodiments, the method or system (e.g. muscarinic
antagonist, optionally in combination with a beta 2-agonist, administered
at a high concentration and/or with a high efficiency nebulizer) provides
an enhanced duration of therapeutic effect, as determined by the amount
of time that a spirometric parameter (e.g. FEV1, trough FEV1)
is above a predetermined threshold after therapy is administered. In some
embodiments, the predetermined threshold is at least about 5% above
baseline, at least about 10% above baseline, at least about 15% above
baseline, at least about 20% above baseline, at least about 25% above
baseline. In some specific embodiments, the threshold is about 15% above
baseline. In some specific embodiments, the threshold is about 10% above
baseline. In some embodiments, the threshold is 50 mL, 100 mL, 150 mL or
more than about 150 mL above baseline. In some specific embodiments, the
threshold is about 100 mL above baseline. Baseline can be determined by
either a one-time reference to the spirometric parameter (e.g. FEV1)
immediately prior to administration of API, or by reference to the
spirometric parameter level at several time periods during the study
following administration of placebo to a predetermined set of patients.
In some embodiments, baseline is determined based on the level of
spirometric parameter (e.g. FEV1) immediately prior to
administration to the patient of muscarinic antagonist administered at a
high concentration and/or with a high efficiency nebulizer. In some
embodiments, baseline is determined by reference to the level of
spirometric parameter (e.g. FEV1) at several time periods (e.g., 12
hours, 24 hours) during evaluation of certain patients following placebo
administration, with the simultaneous evaluation of other patients
administered a muscarinic antagonist administered at a high concentration
and/or with a high efficiency nebulizer.

[0206] In some embodiments, a duration of therapeutic effect is the period
during which FEV1 is at least about 5% above baseline, at least
about 10% above baseline, at least about 15% above baseline, at least
about 20% above baseline, at least about 25% above baseline. In some
specific embodiments, the duration of therapeutic effect is the amount of
time that the FEV1 is at least 15% above baseline. In some specific
embodiments, the duration of therapeutic effect is the amount of time
that the FEV1 is at least 10% above baseline. In some specific
embodiments, the duration of therapeutic effect is the amount of time
that the FEV1 is at least 50 mL, 100 mL, or 150 mL above baseline.
In some embodiments, a duration of therapeutic effect is the period
during which FEV1/FVC is at least about 5% above baseline, at least
about 10% above baseline, at least about 15% above baseline, at least
about 20% above baseline, at least about 25% above baseline. In some
embodiments, the duration of therapeutic effect is the amount of time
that the FEV1/FVC is at least 15% above baseline. In some
embodiments, a duration of therapeutic effect is the period during which
PEF is at least about 5% above baseline, at least about 10% above
baseline, at least about 15% above baseline, at least about 20% above
baseline, at least about 25% above baseline. In some embodiments, the
duration of therapeutic effect is the amount of time that the PEF is at
least 15% above baseline. In some embodiments, a duration of therapeutic
effect is the period during which FEF25-75 is at least about 5%
above baseline, at least about 10% above baseline, at least about 15%
above baseline, at least about 20% above baseline, at least about 25%
above baseline. In some embodiments, the duration of therapeutic effect
is the amount of time that the FEF25-75 is at least 15% above
baseline. In some embodiments, a duration of therapeutic effect is the
period during which FEF25-50 is at least about 5% above baseline, at
least about 10% above baseline, at least about 15% above baseline, at
least about 20% above baseline, at least about 25% above baseline. In
some embodiments, the duration of therapeutic effect is the amount of
time that the FEF25-50 is at least 15% above baseline. In some
embodiments, a duration of therapeutic effect is the period during which
FIF25-75 is at least about 5% above baseline, at least about 10%
above baseline, at least about 15% above baseline, at least about 20%
above baseline, at least about 25% above baseline. In some embodiments,
the duration of therapeutic effect is the amount of time that the
FIF25-75 is at least 15% above baseline. In some embodiments, a
duration of therapeutic effect is the period during which FIF25-50
is at least about 5% above baseline, at least about 10% above baseline,
at least about 15% above baseline, at least about 20% above baseline, at
least about 25% above baseline. In some embodiments, the duration of
therapeutic effect is the amount of time that the FIF25-50 is at
least 15% above baseline.

[0207] A significantly greater, or greater, duration of therapeutic
effect, indicates that the method or system (e.g. a high efficiency
nebulizer-administered muscarinic antagonist) provides an increased
period of time the spirometric parameter is above a predetermined
threshold of about 5% above baseline, about 10% above baseline, about 15%
above baseline, about 20% above baseline, about 25% above baseline,
especially about 15% above baseline, for one or more of the spirometric
parameters compared to the same spirometric parameter obtained with
substantially the same nominal dose of drug administered with a different
inhalation device, e.g. a conventional nebulizer. In some embodiments,
the threshold for the spirometric parameter (e.g. FEV1, or trough
FEV1) is 50 mL, 100 mL, 150 mL or more than about 150 mL above
baseline. In some specific embodiments, the threshold is about 100 mL
above baseline.

[0208] "About the same" duration of therapeutic effect means that the
method or system (e.g. a high efficiency nebulizer-administered
muscarinic antagonist, optionally in combination with a beta 2-agonist)
provides substantially the same period of time that the spirometric
parameter is above a predetermined threshold of about 5% above baseline,
about 10% above baseline, about 15% above baseline, about 20% above
baseline, about 25% above baseline, or especially about 15% above
baseline, for one or more of the above spirometric parameters compared to
the same spirometric parameter obtained with a substantially greater
nominal dose of the muscarinic antagonist administered with a different
inhalation device, e.g. conventional nebulizer (reference
administration).

[0209] In some embodiments, an inhalation solution described herein (e.g.
a LABA or a muscarinic antagonist (LAMA) in combination with a LABA
inhalation solution administered with a conventional or high efficiency
nebulizer) provides a duration of therapeutic effect of at least about 12
hr, about 12 hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr
to about 24 hr, or at least about 24 hr, in some embodiments the duration
of therapeutic effect is at least about 12, 18, 20, 24, 28, 30, 32 or 36
hr.

[0210] In some embodiments in which the muscarinic antagonist combined
with a LABA is administered with a high efficiency nebulizer, a reference
condition is administration of substantially the same combination with a
conventional nebulizer. In some embodiments, a reference condition for
administration of a combination of muscarinic antagonist is
administration of the muscarinic antagonist alone (same or higher dose),
the LABA alone (same or higher dose) or the combination of muscarinic
antagonist and LABA (one or both at a higher dose) with the same
nebulizer.

[0211] A time to onset of therapeutic effect is the time for the
spirometric parameter to reach a predetermined threshold of about 5%
above baseline, about 10% above baseline, about 15% above baseline, about
20% above baseline, or about 25% above baseline, especially about 15%
above baseline for one or more of the spirometric parameters of a LABA or
a muscarinic antagonist in combination with a LABA administered with an
inhalation device. An enhanced time to onset of therapeutic effect
relates to the increased ability of a pharmaceutical agent to relieve the
symptoms of an airway respiratory disorder, e.g. COPD. The enhanced time
to onset of therapeutic effect may be a measure of the FEV1,
FEV1/FVC, PEF, FEF25-75, FEF25-50, FIF25-75, or
FIF25-50 levels.

[0212] A significantly shorter, or shorter, time to onset of therapeutic
effect, in some embodiments, means that the method or system (a LABA or a
muscarinic antagonist in combination with a LABA administered with a
conventional or high efficiency nebulizer) provides for a shortened
period of time for one or more spirometric parameters (e.g. FEV1) to
reach a predetermined threshold of about 5% above baseline, about 10%
above baseline, about 15% above baseline, about 20% above baseline, or
about 25% above baseline, especially about 15% above baseline, for one or
more of the spirometric parameters compared to the same spirometric
parameter(s) obtained with substantially the same nominal dose of the
drug solution administered under a reference condition. In some
embodiments, "about the same" time to onset of therapeutic effect means
the method or system (e.g. administration of a LABA or a muscarinic
antagonist in combination with a LABA with conventional or a high
efficiency nebulizer) provides for substantially the same period of time
for the spirometric parameter to reach a predetermined threshold of about
5% above baseline, about 10% above baseline, about 15% above baseline, or
about 20% above baseline for one or more of the spirometric parameters
compared to the same spirometric parameter obtained under a reference
condition.

[0213] An inhalation solution that provides an onset of therapeutic effect
of less than about 30 minutes, less than about 25 minutes, less than
about 20 minutes, less than about 15 minutes, or less than about 10
minutes, in some embodiments, refers to an amount of time for the
spirometric parameter to reach a predetermined threshold of about 5%
above baseline, about 10% above baseline, about 15% above baseline, or
about 20% above baseline.

[0214] In some embodiments, the methods or systems are provided for the
treatment of acute exacerbations of Chronic Obstructive Pulmonary Disease
(COPD), chronic bronchitis, and optionally emphysema in a patient,
comprising administering to the patient a nominal dose of a LABA or a
muscarinic antagonist in combination with a LABA in an aqueous inhalation
solution at a concentration of a LABA or a muscarinic antagonist in
combination with a LABA sufficient to provide a rapid onset of
therapeutic effect and a long duration of therapeutic effect. In some
embodiments, the rapid onset of therapeutic effect is less than about 30
minutes, less than about 25 minutes, less than about 20 minutes, less
than about 15 minutes or less than about 10 minutes. In some embodiments,
the long duration of therapeutic effect is at least about 12 hr to about
24 hr, about 18 hr to about 24 hr, about 20 hr to about 24 hr or at least
about 18, 20, 24, 28, 30, 32 or 36 hr.

[0215] A time to maximum therapeutic effect means the amount of time for a
preselected spirometric parameter to reach its peak level. In some
embodiments, an enhanced time to maximum therapeutic effect means that
administration of a LABA or a muscarinic antagonist in combination with a
LABA with a high efficiency nebulizer, at a high concentration or both,
results in a faster time to maximum therapeutic effect than would a dose
of the LABA or the muscarinic antagonist in combination with a LABA
administered with a conventional nebulizer. The parameters used to
determine an enhanced time to maximum therapeutic effect may be one or
more of FEV1, FEV1/FVC, PEF, FEF25-75, FEF25-50,
FIF25-75, or FIF25-50.

[0216] Reduction in Adverse Side Effects

[0217] Conventional COPD therapy employing a LABA or a muscarinic
antagonist with conventional inhalation devices and conventional
nebulizers often results in deposition of pharmaceutically active
ingredient in sections distinct from the pulmonary lung, e.g., mouth,
throat, stomach, and optionally a esophagus. This is a result of the
presence of muscarinic receptors on peripheral systems other than the
pulmonary lung, for example in salivary glands, stomach, and elsewhere.
Therefore the use of systemically active muscarinic antagonists is
limited by side-effects such as, but not limited to, xerostomia (dry
mouth), urinary hesitancy and retention, blurred vision, tachycardia,
dizziness, insomnia, impotence, mental confusion and optionally a
excitement, headache, anxiety, hypotension or palpitations.

[0218] In the present invention, the bronchodilation and other beneficial
actions of a muscarinic antagonist in combination with a LABA are
produced by an inhaled agent providing for a high therapeutic index for
activity in the lung, i.e. lung deposition, compared with deposition of
muscarinic antagonist in non-pulmonary regions, i.e. periphery
compartments, mouth and pharynx. The present invention further provides
for an inhalable muscarinic antagonist with low bioavailability in areas
within a patient other than the lung (e.g. systemic bioavailability,
local oropharyngeal or gastric regions), resulting in a decreased
incidence and/or severity of systemic and/or local toxicity and/or side
effects. A practitioner of ordinary skill can quantify a reduction in
adverse side effects by measuring the incidence and/or severity of
systemic and/or local toxicity and/or side effects in a given patient or
patient population.

[0219] A reduced, or decreased, incidence or severity of systemic and/or
local toxicity and/or side effects means that the method or system (e.g.
a LABA or a muscarinic antagonist in combination with a LABA,
administered with a conventional or high efficiency nebulizer) provides a
decreased incidence and/or severity of systemic and/or local toxicity
and/or side effects (for example dry mouth) in a given patient or patient
population compared to a given reference therapy. In some embodiments,
the reference therapy is administration of a LABA optionally in
combination with a muscarinic antagonist with a conventional nebulizer.
Some embodiments provide a method for the treatment or prophylaxis of a
respiratory condition in a patient, comprising administering to the
patient a nominal dose of a LABA or of a combination a muscarinic
antagonist and LABA which, when administered with a high efficiency
nebulizer, provides a calculated respirable dose of a LABA or a
combination of a muscarinic antagonist and a LABA with a high efficiency
nebulizer, wherein the calculated respirable dose of the LABA or
combination of a muscarinic antagonist and a LABA administered with the
high efficiency nebulizer demonstrates a decreased incidence and/or
severity of systemic and/or local toxicity and/or side effects in the
patient as compared to substantially the same calculated respirable dose
of the LABA or combination of a muscarinic antagonist and a LABA
administered with a conventional nebulizer. Some embodiments provide a
method for the treatment or prophylaxis of a respiratory condition in a
patient, comprising administering to the patient a nominal dose of said
LABA or said combination of muscarinic antagonist and LABA which, when
administered with a high efficiency nebulizer, provides a measured
deposited dose of said LABA or said combination of a muscarinic
antagonist and a LABA with a high efficiency nebulizer, wherein the
measured deposited dose of a LABA or a combination of a muscarinic
antagonist and a LABA administered with the high efficiency nebulizer
demonstrates a decreased incidence and/or severity of systemic and/or
local toxicity and/or side effects in the patient as compared to
substantially the same measured deposited dose of a LABA or a combination
of a muscarinic antagonist and a LABA administered with a conventional
nebulizer. Some embodiments provide a system for performing the foregoing
methods.

[0221] In some embodiments, the method or system (e.g. LABA, with a high
efficiency nebulizer or administration of a muscarinic antagonist in
combination with a LABA, with a conventional or high efficiency
nebulizer) provides for administering a muscarinic antagonist at a
concentration of at least about 0.25 to about 2.0 mg/mL, at least about
0.25 mg/mL, at least about 0.5 mg/mL, at least about 1.0 mg/mL, at least
about 1.5 mg/mL, or at least about 2.0 mg/mL and the muscarinic
antagonist demonstrates a decreased incidence and optionally a severity
of incidence and/or severity of systemic and/or local toxicity and/or
side effects (for example dry mouth) in the patient as compared to
substantially the same nominal dose of the muscarinic antagonist
administered at a substantially lower concentration. In other
embodiments, the concentration of muscarinic antagonist is about 0.05 to
about 2.0 mg/mL, about 0.1 to 2.0 mg/mL, about 0.2 to about 2.0 mg/mL,
about 0.05 to about 1.0 mg/mL, about 0.1 to about 1.0 mg/mL or about 0.2
to about 1.0 mg/mL. In some embodiments, the method or system (e.g.
administration of a muscarinic antagonist in combination with a LABA,
with a high efficiency nebulizer and/or at a high concentration) provides
a method and/or inhalation system for administration of a muscarinic
antagonist in a volume of about 0.5 mL or less, 1 mL or less, 1.5 mL or
less, or 2.0 mL or less and wherein the muscarinic antagonist
demonstrates less incidence and/or severity of systemic and/or local
toxicity and/or side effects (for example dry mouth) in the patient as
compared to substantially the same nominal dose of the muscarinic
antagonist administered in a substantially higher volume of solution.

[0222] In some embodiments, the method or system (e.g., a combination of
muscarinic antagonist with a LABA, with a conventional or high efficiency
nebulizer) provides for methods and inhalation systems for reducing at
least one side effect of the LABA and/or of the muscarinic antagonist and
providing a duration of therapeutic effect of at least about 12 hr, about
12 hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr to about 24
hr, or at least about 12, 18, 24, 28, 30, 32 or 36 hours. In some
embodiments, the method or system (e.g., administration of a LABA or a
muscarinic antagonist in combination with a LABA, with a high efficiency
nebulizer and/or at a high concentration) provides for co-administration
of other drugs and optionally excipients, for example an organic acid,
such as ascorbic acid, citric acid or a mixture of both, pilocarpine,
cevimeline or carboxymethylcellulose, or a mucolytic compound.

[0223] Enhanced Lung Deposition

[0224] Muscarinic receptors and beta 2-adrenoreceptors are widely
distributed throughout the body. The ability to apply these active
pharmaceutical agents (APIs) locally to the respiratory tract with
sufficient lung deposition is particularly advantageous, as it would
allow for administration of lower doses of the drug fostering increased
patient compliance

[0225] The principle advantage of administration of a nebulized LABA or
combination of muscarinic antagonist and LABA solution with a high
efficiency nebulizer over other methods of pulmonary delivery of APIs is
that such administration offers more efficient delivery of higher doses
of said combination compared to conventional inhalation methods and
systems, resulting in greater efficacy and a reduced incidence and/or a
severity of side effects in the patient. In some embodiments, this allows
for use of a higher nominal dose of API, as more efficient delivery of
API to the lung is expected to result in lower proportional deposition in
the mouth and pharynx, leading to reduced side effects from
extrapulmonary (e.g. gastrointestinal) absorption of the API. In other
embodiments, more efficient pulmonary delivery of API with a high
efficiency nebulizer can permit use of a reduced nominal dose, relative
to a nominal dose that is effective when administered with a conventional
nebulizer, as more efficient lung delivery of the API means that more of
the nominal dose reaches the target tissue and gives rise to the desired
therapeutic effect. A more efficient delivery of said LABA or said
combination is evidenced by direct delivery and deposition of the
combination to the site of action, i.e. the lung (as used herein, "lung"
refers to either or both the right and left lung organs). It can be
assumed that substantially all of the combination delivered at the
receptor site in the lungs will be absorbed into the blood plasma of the
patient.

[0226] A lung deposition of 30% means 30% of the active ingredient in the
inhalation device just prior to administration is deposited in the lung.
A lung deposition of 60% means 60% of the active ingredient in the
inhalation device just prior to administration is deposited in the lung,
and so forth. Lung deposition can be determined using methods of
scintigraphy or deconvolution of pharmacokinetic data. In some
embodiments, the present invention provides for methods and inhalation
systems for the treatment or prophylaxis of a respiratory condition in a
patient, comprising administering to the patient a nominal dose of a LABA
solution or a muscarinic antagonist in combination with a LABA with a
high efficiency nebulizer inhalation device wherein administration of the
muscarinic antagonist in combination with the LABA with the inhalation
device provides lung deposition of the muscarinic antagonist in
combination with a LABA of at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 60%, about 30% to about 60%, about 30% to about 55%,
about 30% to about 50%, about 30% to about 40%, about 30% to about 90%,
about 40% to about 80%, about 50% to about 60%, or about 60% to about 70%
based on the nominal dose of the LABA or of the muscarinic antagonist in
combination with the LABA. In some embodiments, the present invention
provides for methods and inhalation systems for the treatment or
prophylaxis of a respiratory condition in a patient, comprising
administering to the patient a nominal dose of a LABA or of a muscarinic
antagonist in combination with the LABA in an aqueous inhalation solution
with an inhalation device wherein administration of the LABA or the
muscarinic antagonist in combination with a LABA with the inhalation
device provides lung deposition of the LABA or the muscarinic antagonist
and the LABA of at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about 60%,
about 20% to about 40%, about 25% to about 35%, about 25% to about 30%,
about 35% to about 90%, about 40% to about 80%, about 50% to about 60%,
or about 60% to about 70% based on the nominal dose of the LABA or the
muscarinic antagonist and the LABA.

[0227] Aerosol particle/droplet size is one of the most important factors
determining the deposition of aerosol drugs in the airways. The portion
of an aerosol that has the highest probability of bypassing the upper
airway and depositing in the lung measures between 1 and 5 μm.
Particles larger than this are generally deposited in the oropharyngeal
region and are swallowed, while sub-micron particles do not carry much
drug and may be exhaled before deposition takes place. Smaller particles
tend to deposit more peripherally in the lung than coarser particles,
which may lead to a different clinical response. Consequently,
differences in particle size of the aerosol emitted from inhalation
devices may account for some of the variability in therapeutic efficacy
and safety. Measurement of particle size, therefore, has an important
role in guiding product development and in quality control of the
marketed product.

[0228] The distribution of aerosol particle/droplet size can be expressed
in terms of either or both of:

[0229] The Mass Median Aerodynamic Diameter (MMAD) and the Geometric
Standard Deviation (GSD), wherein the MMAD is the droplet size at which
half of the mass of the aerosol is contained in smaller droplets and half
in larger droplets and the GSD is the geometric standard deviation of the
particle population

[0230] The Fine Particle Fraction (FPF), which is the fraction of
particles (which may be expressed as a percentage) that are <5 μm
in diameter.

[0231] These measures have been used for comparisons of the in vitro
performance of different inhaler device and drug combinations. In
general, the higher the fine particle fraction, the higher the proportion
of the emitted dose that is likely to reach the lung.

[0232] There are two main methods used to measure aerosol deposition in
the lungs. First, γ-scintigraphy is performed by radiolabeling the
drug with a substance like 99m-technetium, and scanning the subject after
inhalation of the drug. This technique has the advantage of being able to
quantify the proportion of aerosol inhaled by the patient, as well as
regional distribution in the upper airway and lungs. Second, since most
of the drug that is deposited in the lower airways will be absorbed into
the bloodstream, pharmacokinetic techniques are used to measure lung
deposition. This technique can assess the total amount of drug that
interacts with the airway epithelium and is absorbed systemically, but
will miss the small portion that may be expectorated or swallowed after
mucociliary clearance, and does not fully describe regional distribution.
Therefore, γ-scintigraphy and pharmacokinetic studies are in many
cases considered complementary.

[0233] The relationship between pulmonary deposition of inhaled beta
2-agonists and therapeutic effect is now well-established, since the
immediate effects of these agents on the airways are relatively easy to
measure. As the pulmonary dose-response curve for the beta 2-agonists is
sigmoidal (i.e. an initial slope followed by a plateau), increasing the
dose deposited in the lung will elicit an increased therapeutic effect
only if the initial dose was on the rising slope of the dose-response
curve.

[0234] Lung deposition of a particular drug is influenced by the mass of
fluid contained in the nebulized droplets administered to a patient with
a particular Mass Median Aerodynamic Diameter (MMAD) and Geometric
Standard Deviation (GSD). In general, there is an inverse relationship
between the average MMAD and GSD of a particular nebulizer's emitted
droplets and deposition of the droplets in a patient's lung. Therefore, a
smaller MMAD results in an increased likelihood of lung deposition in a
patient. Likewise, when the MMAD is in the range of about 4-5 μm, a
narrower GSD results in a higher degree of lung deposition, since a
higher percentage of particles will be under 5 μm in diameter. It is
believed that, in general, aerosol particles greater than ˜10 μm
in aerodynamic diameter deposit primarily in the oropharynx and are
swallowed rather than reaching the lungs. Because of the plausible link
between MMAD and GSD values and eventual deposition site within the
respiratory tract, smaller MMAD and GSD values may affect both the safety
(by reducing non-pulmonary deposition and possibly thereby reducing local
and potentially systemic effects) and the efficacy (by increasing the
amount of drug actually deposited in the lungs) of drug products
administered with such high efficiency inhalation devices.
Laser-diffraction provides for an in-vitro method of determining MMAD and
GSD data, which can then be plotted onto what usually results in a
log-normal shaped curve (depicting mass distribution % on the Y-axis and
droplet diameter on the X-axis). Laser-diffraction methods are well-known
to one of ordinary skill in the art. In addition to laser-diffraction
methods, in-vitro data for MMAD and GSD can also be measured using
cascade impaction or time-of-flight analytical methods, both of which are
known to one of ordinary skill in the art.

[0235] In some embodiments, administration of the LABA or the combination
of muscarinic antagonist and LABA with the high efficiency nebulizer
provides a Geometric Standard Deviation (GSD) of emitted droplet size
distribution of the solution administered with a high efficiency
nebulizer of about 1.1 to about 2.1, about 1.2 to about 2.0, about 1.3 to
about 1.9, about 2.2, at least about 1.4 to about 1.8, at least about 1.5
to about 1.7, about 1.4, about 1.5, or about 1.6. In some embodiments,
administration of API with a high efficiency nebulizer provides a Mass
Median Aerodynamic Diameter (MMAD) of droplet size of the solution
emitted with the high efficiency nebulizer of about 1 μm to about 5
μm, about 2 to about 4 μm, or about 3.5 to about 4.5 μm.

[0236] Respirable Fraction (RF), Emitted Dose (ED), Respirable Dose (RD)
and the Respirable Dose Delivery Rate (RDDR) provide technical dimensions
for the efficiency of a nebulizer inhalation device. RF is a generally
accepted estimate of lung deposition within the medical community. RF
represents the fraction of the delivered aerosol dose, or inhaled mass,
with droplets of diameter less than 5.0 μm. Droplets of less than 5.0
μm in diameter are considered to penetrate to the lung. In some
embodiments, administration of the LABA or muscarinic antagonist (e.g.
LAMA) in combination with a LABA with an aqueous inhalation device
provides a respirable fraction (RF) of API of at least about 60%, at
least about 65%, at least about 70%, at least about 75%, at least about
80%, at least about 85%, at least about 90%, about 60% to about 95%,
about 65% to about 95%, or about 70% to about 90%.

[0237] The Emitted Dose (ED) portion of drug that is actually emitted from
the mouthpiece of the device. The ED of the muscarinic antagonist in
combination with a LABA is to be tested under simulated breathing
conditions using a standardized bench setup, which are known to one of
skill in the art. In some embodiments, the ED of the LABA or combination
of muscarinic antagonist and LABA is at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, about 30% to about 60%, about 30% to about
55%, about 30% to about 50%, about 30% to about 40%, about 30% to about
75%, about 40% to about 70%, or about 45% to about 60%.

EXAMPLES

[0238] The following non-limiting examples provide ingredients, processes
and procedures for practicing the systems and methods herein, and are
intended to be illustrative of the invention described and claimed
herein. The procedures below describe some embodiments of methods of
delivery of a nebulized long-acting beta 2-agonist (LABA) with a high
efficiency or a muscarinic antagonist in combination with a nebulized
beta 2-agonist aqueous solution (in combination therapy) with a high
efficiency nebulizer, as described herein.

Example 1

Randomized, Cross-Over, Single Dose Study

[0239] Approximately twelve (12) adult COPD patients of ages 40-75 years
are randomized to receive five treatments in a crossover design: (1) 20
μg formoterol administered with a conventional nebulizer; (2) 5 μg
of formoterol administered with a high efficiency nebulizer; (3) 7.5
μg of formoterol administered with a high efficiency nebulizer; (4) 10
μg of formoterol administered with a high efficiency nebulizer: and
(5) 20 μg of formoterol administered with a high efficiency nebulizer.

[0240] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the formoterol to the
patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0241] A projected outcome is that formoterol administered to patients
with a high efficiency nebulizer at the tested doses produces in a
patient or population of patients a therapeutic effect (i.e. at least one
spirometry measurement, e.g. FEV1 is at least 10% and/or 100 mL
above baseline and/or placebo for a significant period of time, e.g.
12-24 hours.)

[0242] Another projected outcome is that formoterol produces clinically
meaningful bronchodilation of at least 24 hours when administered with a
high efficiency nebulizer, wherein the same or higher dose of formoterol
produces less than 24 hours of clinically meaningful bronchodilation when
administered with a conventional nebulizer.

[0243] Another projected outcome is that a lower dose formoterol
administered to patients with a high efficiency nebulizer produces in a
patient or population of patients improved or similar therapeutic effects
with an improved adverse event profile and/or improved side effects as a
measure of cellular activity (changes in serum potassium, glucose levels)
as compared to a selected dose of formoterol administered with a
conventional nebulizer.

[0244] Approx 50 adult COPD patients of ages 40-75 years are randomized to
one of five treatment groups: (1) 20 μg formoterol administered B.I.D.
with a conventional nebulizer; (2) 10 μg of formoterol administered
B.I.D. with a high efficiency nebulizer; (3) 10 μg of formoterol
administered Q.D. with a high efficiency nebulizer; (4) 5 μg of
formoterol administered Q.D. with a high efficiency nebulizer; (5)
placebo administered B.I.D. with a high efficiency nebulizer.

[0245] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the formoterol to the
patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0246] A projected outcome is that formoterol administered to patients
with a high efficiency nebulizer at the tested doses produces in a
patient or population of patients a therapeutic effect (i.e. at least one
spirometry measurement, e.g. FEV1 is at least 10% and/or 100 mL
above baseline and/or placebo for a significant period of time, e.g.
12-24 hours.)

[0247] Another projected outcome is that formoterol produces clinically
meaningful bronchodilation of at least 24 hours when administered with a
high efficiency nebulizer, wherein the same or higher dose of formoterol
produces less than 24 hours of clinically meaningful bronchodilation when
administered with a conventional nebulizer.

[0248] Another projected outcome is that lower dose formoterol
administered to patients with a high efficiency nebulizer produces in a
patient or population of patients improved or similar therapeutic effects
with an improved adverse event profile and/or improved side effects as a
measure of cellular activity (changes in serum potassium, glucose levels)
as compared to a selected dose of formoterol administered with a
conventional nebulizer.

[0249] Approx twelve (12) adult COPD patients of ages 40-75 years are
randomized to receive five treatments in a cross-over design: (1) 15
μg arformoterol administered with a conventional nebulizer; (2) 8
μg of arformoterol administered with a high efficiency nebulizer; (3)
4 μg of arformoterol administered with a high efficiency nebulizer;
(4) 2 μg of arformoterol administered with a high efficiency nebulizer
and (5) nebulized placebo.

[0250] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the arformoterol to
the patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0251] A projected outcome is that arformoterol administered to patients
with a high efficiency nebulizer at the tested doses produces in a
patient or population of patients a therapeutic effect (i.e. at least one
spirometry measurement, e.g. FEV1 is at least 10% and/or 100 mL
above baseline and/or placebo for a significant period of time, e.g.
12-24 hours.)

[0252] Another projected outcome is that arformoterol produces clinically
meaningful bronchodilation of at least 24 hours when administered with a
high efficiency nebulizer, wherein the same or higher dose of
arformoterol produces less than 24 hours of clinically meaningful
bronchodilation when administered with a conventional nebulizer.

[0253] Another projected outcome is that lower dose arformoterol
administered to patients with a high efficiency nebulizer produces in a
patient or population of patients improved or similar therapeutic effects
with an improved adverse event profile and/or improved side effects as a
measure of cellular activity (changes in serum potassium, glucose levels)
as compared to a selected dose of arformoterol administered with a
conventional nebulizer.

[0254] Approx fifty (50) adult COPD patients of ages 40-75 years are
randomized to one of five treatment groups: (1) 15 μg arformoterol
administered B.I.D. with a conventional nebulizer; (2) 8 μg of
arformoterol administered B.I.D. with a high efficiency nebulizer; (3) 8
μg of arformoterol administered Q.D. with a high efficiency nebulizer;
(4) 4 μg of arformoterol administered B.I.D. with a high efficiency
nebulizer; and (5) placebo administered B.I.D. with a high efficiency
nebulizer.

[0255] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the arformoterol to
the patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0256] A projected outcome is that arformoterol administered to patients
with a high efficiency nebulizer at the tested doses produces in a
patient or population of patients a therapeutic effect (i.e. at least one
spirometry measurement, e.g. FEV1 is at least 10% and/or 100 mL
above baseline and/or placebo for a significant period of time, e.g.
12-24 hours.)

[0257] Another projected outcome is that arformoterol produces clinically
meaningful bronchodilation of at least 24 hours when administered with a
high efficiency nebulizer, wherein the same or higher dose of
arformoterol produces less than 24 hours of clinically meaningful
bronchodilation when administered with a conventional nebulizer.

[0258] Another projected outcome is that lower dose arformoterol
administered to patients with a high efficiency nebulizer produces in a
patient or population of patients improved or similar therapeutic effects
with an improved adverse event profile and/or improved side effects as a
measure of cellular activity (changes in serum potassium, glucose levels)
as compared to a selected dose of arformoterol administered with a
conventional nebulizer.

Example 5

Randomized, Placebo-Controlled, Parallel-Group, Multi-Dose Study

[0259] At least about three hundred (300) adult human COPD patients of
ages >45 years are randomized to one of three treatment groups: (1)
formoterol or arformoterol administered with a high efficiency nebulizer;
(2) formoterol or arformoterol administered with a conventional
nebulizer; (3) placebo.

[0260] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the arformoterol to
the patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0261] A projected outcome is that formoterol or arformoterol administered
to patients with a high efficiency nebulizer at the tested doses produces
in a patient or population of patients a therapeutic effect (i.e. at
least one spirometry measurement, e.g. FEV1 is at least 10% and/or
100 mL above baseline and/or placebo for a significant period of time,
e.g. 12-24 hours.)

[0262] Another projected outcome is that formoterol or arformoterol
produces clinically meaningful bronchodilation of at least 24 hours when
administered with a high efficiency nebulizer, wherein the same or higher
dose of formoterol or arformoterol produces less than 24 hours of
clinically meaningful bronchodilation when administered with a
conventional nebulizer.

[0263] Another projected outcome is that a lower dose formoterol or
arformoterol administered to patients with a high efficiency nebulizer
produces in a patient or population of patients improved or similar
therapeutic effects with an improved adverse event profile and/or
improved side effects as a measure of cellular activity (changes in serum
potassium, glucose levels) as compared to a selected dose of formoterol
or arformoterol administered with a conventional nebulizer.

Example 6

Randomized, Cross-Over, Single Dose Study

[0264] At least about eight (8) adult healthy human volunteers (patients)
are randomized to receive four treatments in a cross-over design: (1) 50
μg of salmeterol; (3) 25 μg of salmeterol administered with a high
efficiency nebulizer; (4) 12 μg of salmeterol administered with a high
efficiency nebulizer. Lung function is determined by spirometry, which
measures e.g. FEV1 and optionally other suitable spirometry
parameters, such as FEV1 AUC.

[0265] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the salmeterol to the
patients. Additionally, the patients are monitored for any adverse
events, such as tremor, as well as for vital signs and electrocardiogram.
COPD symptom scores are obtained by administering to each patient a
conventional or proprietary symptom score instrument.

[0266] A projected outcome is that salmeterol administered to patients
with a high efficiency nebulizer at the tested doses produces in a
patient or population of patients a therapeutic effect (i.e. at least one
spirometry measurement, e.g. FEV1 is at least 10% and/or 100 mL
above baseline and/or placebo for a significant period of time, e.g.
12-24 hours.)

[0267] Another projected outcome is that salmeterol produces clinically
meaningful bronchodilation of at least 24 hours when administered with a
high efficiency nebulizer, wherein the same dose of salmeterol produces
less than 24 hours of clinically meaningful bronchodilation when
administered with a conventional nebulizer, metered dose inhaler, or dry
powder inhaler.

[0268] Another projected outcome is that lower dose salmeterol
administered to patients with a high efficiency nebulizer produces in a
patient or population of patients improved or similar therapeutic effects
with an improved adverse event profile and/or improved side effects as a
measure of cellular activity (changes in serum potassium, glucose levels)
as compared to a selected dose of salmeterol administered with a
conventional nebulizer.

[0269] Approx. 36 adult COPD patients of ages 40-75 years are randomized
to receive single dose treatments in a crossover design using a high
efficiency nebulizer: (1) a first dose of glycopyrrolate (e.g. a dose in
the range of 100-300 meg); (2) a first dose of formoterol (racemate)
(e.g. a dose in the range of 5-20 meg); (3) the first dose of
glycopyrrolate from (1) and the first dose of formoterol (racemate) from
(2); (4) the first dose of glycopyrrolate from (1) and a second dose of
formoterol (racemate), which is approximately half the formoterol dose in
(2); (5) a second dose of glycopyrrolate, which is approximately half the
first glycopyrrolate dose from (1), and the first dose of formoterol
(racemate) from (2); (6) the second dose of glycopyrrolate (approximately
half the first dose from (1)) and the second dose of formoterol
(racemate) (approximately half the dose in (2)); (7) a third dose of
glycopyrrolate, which is approximately one quarter the dose in (1), and
the first dose of formoterol from (2); (8) the third dose of
glycopyrrolate (approximately one quarter of the dose in (1)), and the
second dose of formoterol (approximately half the dose in (2)); (9)
Placebo.

[0270] Blood and/or urine samples are drawn immediately prior to
administration of glycopyrrolate and formoterol and at predetermined time
points thereafter. The blood plasma levels of glycopyrrolate in the blood
samples and urine levels of formoterol in the urine are determined and
analyzed to determine the appropriate pharmacokinetic parameters (e.g.
C., Tmax, AUClast, and AUC0-∞) for glycopyrrolate.
Additionally, the patients are monitored for any adverse events as well
as vital signs and electrocardiogram.

[0271] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the arformoterol to
the patients.

[0272] A projected outcome is that administration of a standard dose of
combination of formoterol and glycopyrrolate with a high efficiency
nebulizer will result in significantly improved therapeutic effect
compared to administration of formoterol with a nebulizer as a
monotherapy and/or compared to administration of glycopyrrolate with a
nebulizer as a monotherapy. Another projected outcome is that combined
glycopyrrolate and formoterol therapy results in at least 24 hours of
clinically meaningful bronchodilation with acceptable side effects.
Another projected outcome is that glycopyrrolate and formoterol therapy
results in reduced side effects as compared to dosing of either of the
therapeutic agents separately. A further projected outcome is that
combined dosing of a glycopyrrolate and formoterol permits dosing at less
than half a standard dose of one or both of the glycopyrrolate and/or
formoterol.

[0274] Blood and/or urine samples are drawn immediately prior to
administration of glycopyrrolate and arformoterol and at predetermined
time points thereafter. The blood plasma levels of glycopyrrolate in the
blood samples and urine levels of arformoterol in the urine are
determined and analyzed to determine the appropriate pharmacokinetic
parameters (e.g. C., Tmax, AUClast, and AUCO-∞) for
glycopyrrolate. Additionally, the patients are monitored for any adverse
events as well as vital signs and electrocardiogram.

[0275] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the combination of
glycopyrrolate and arformoterol to the patients.

[0276] A projected outcome is that administration of a standard (approved)
dose of arformoterol with a high efficiency nebulizer will result in a
therapeutic effect for at least 24 hr. Another projected outcome is that
administration of a standard dose of combination of arformoterol and
glycopyrrolate with a high efficiency nebulizer will result in
significantly improved therapeutic effect compared to administration of
arformoterol with a nebulizer as a monotherapy and/or compared to
administration of glycopyrrolate with a nebulizer as a monotherapy.
Another projected outcome is that combined glycopyrrolate and
arformoterol therapy permits 24 hour dosing. Another projected outcome is
that combined glycopyrrolate and arformoterol therapy results in reduced
side effects as compared to dosing of either of the therapeutic agents
separately. A further projected outcome is that combined dosing of
glycopyrrolate and arformoterol permits dosing at less than half a
standard dose of one or both of the glycopyrrolate and/or the
arformoterol.

[0277] Another projected outcome is that arformoterol administered to
human patients with a high efficiency nebulizer at a lower dose produces
in a patient or population of patients a pharmacokinetic profile
characterized by a Cmax, AUClast and/or AUCO-∞ that
is comparable to, or greater than, a Cmax, AUClast and/or
AUCO-∞ obtained with a higher dose of arformoterol
administered with a conventional nebulizer.

[0278] Another projected outcome is that arformoterol administered to
human patients with a high efficiency nebulizer produces in a patient or
population of patients an improved adverse event profile as compared to a
comparable or lower dose of arformoterol administered with a conventional
nebulizer.

[0279] Another projected outcome is that arformoterol administered to
human patients with a high efficiency nebulizer produces in a patient or
population of patients higher degree of lung deposition of the
arformoterol as compared to a comparable or higher dose of arformoterol
administered with a conventional nebulizer.

[0281] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the arformoterol to
the patients. Additionally, the patients are monitored for any adverse
events, as well as for vital signs and electrocardiogram.

[0282] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the formoterol to the
patients. A projected outcome is that combined glycopyrrolate and
formoterol therapy permits 24 hour dosing. Another projected outcome is
that combined glycopyrrolate and formoterol therapy results in reduced
side effects as compared to dosing of either of the therapeutic agents
separately. A further projected outcome is that combined dosing of
glycopyrrolate and formoterol permits dosing at less than half a standard
dose of one or both of the glycopyrrolate and/or formoterol.

[0284] Lung function is determined by spirometry, which measures e.g.
FEV1 and optionally other suitable spirometry parameters, such as
FEV1 AUC. Spirometry is conducted immediately before and at
predetermined intervals following administration of the salmeterol to the
patients. A projected outcome is that combined glycopyrrolate and
formoterol therapy permits 24 hour dosing. Another projected outcome is
that combined glycopyrrolate and formoterol therapy results in reduced
side effects as compared to dosing of either of the therapeutic agents
separately. A further projected outcome is that combined dosing of a
glycopyrrolate and formoterol permits dosing at less than half a standard
dose of one or both of glycopyrrolate and/or formoterol.

[0285] While preferred embodiments of the present invention have been
shown and described herein, it will be apparent that such embodiments are
provided by way of example only. Numerous variations, changes, and
substitutions will now occur to those skilled in the art without
departing from the invention. It should be understood that various
alternatives to the embodiments of the invention described herein may be
employed in practicing the invention. It is intended that the following
claims define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.